Toxicity Testing and Risk Assessment
Regulatory Toxicology (the laws and regulations governing the marketing,
transport, and exposure limits of potential poisons) has led to the need
for testing of potential toxicants. These laws and regulations vary
greatly from country to country and for each type of toxicant. The
exact type of tests that must or should be performed are determined, at
least in part, by the risk of potential exposure, the dose or amount during
exposure, the setting of the exposure, persistence of the toxicant and
many other factors.
Toxicity Testing
Data that is used in the regulation of toxicants may be derived from
basic science (bench top or laboratory research) and from epidemiological
sources that collect and correlate specific cases of toxicity to a particular
compound.
When designing basic scientific research, numerous factors must be considered
to ensure a well-designed and productive study, including the physicochemical
properties of the compound, the model (animal species, strain), route of
administration, duration of the study, and controls (positive and negative).
Some of the more common types of toxicity testing are summarised below.
Acute Toxicity Testing -- Often used to determine lethality and acute
effects of a toxicant. These studies typical involve the administration
of successively higher doses to the subjects (one dose per subject).
These tests are often the source of LD50 data and dose:response
relationships.
Subacute or Subchronic Toxicity Testing -- These tests, often involving
multiple exposures to the same subject, extend for 1-3 months. They
indicate slow-onset effects of the toxicant, progressive organ damage,
and are the source of the NOAEL for the toxicant.
Chronic Toxicity Testing -- These tests often involve lifetime exposure
to the toxicant, to examine for chronic effects.
For each of the above paradigms, Good Laboratory Practice (GLP) must be
maintained to ensure the integrity of the study. This includes quality
control and assurance, documentation, and strict adherence to the study
protocol. Additionally, during each of these studies the gathering
of empirical data such as body weights, observance of behavioural changes,
food intake, metabolism, and pathology, which may be auxiliary to the primary
goal of the study, may provide invaluable information on the toxicity of
the compound.
In addition to the above tests, specific studies may also be required
to examine the mutagenic, carcinogenic, reproductive, and teratogenic effects
of the toxicant.
The fallacies of any toxicity tests include extrapolation back to humans
(for both the effects and the exposure limits), appropriateness of the
animal model, and the pitfalls of science (unpredictable and unavoidable
disturbances of the study).
Two specific tests that have become standard for many classes of compounds
are the Draize Eye and Skin tests for irritation and allergenicity.
Skin Testing --
Irritation -- New Zealand White rabbits are the usual model for these
tests. Two areas of the back are shaved. One of these areas
is abraded while the other is left intact. The target compound is
applied to both areas with 0.5 ml of a liquid form or 0.5 Gm of a solid.
The area is covered for 24 hr and rated at 24 hr and 72 hr post-exposure.
These are compared to controls that were treated with vehicle and rated
on 0-4 for the presence of erythema and 0-4 for œdema (0 = none present).
Allergenicity -- Guinea Pigs are the most common model for allergenicity
testing. Six areas are shaved and exposed to the target compound
(area 1 exposed on day 1, area 2 on day 2, et c.). If the
compound elicits an allergic response, then prior exposure (i.e. on day
1) will result in a reaction by day 3, 4, 5, or 6.
Eye Testing (Draize Test) -- New Zealand whites are again used for these
tests. The dose (0.1 ml liquid or 0.1 Gm solid) is place in the conjunctiva
of one eye of the animal (the other eye serves as a negative control) which
is then closed for 1-5 sec. Responses are recorded over the first
24 hours (immediate, 4 hr, 6 hr, 12 hr, 16 hr, et c.) and at 24,
48, and 72 hr post exposure, using the following scale:
Corneal opacity -- 0 - 4
Iris -- 0 - 2 (normal, folded but reactive, non-reactive to light)
Conjunctiva -- 0 -3 for vasodilatation and congestion (reddest = 3)
Chemosis -- 0 - 4 for œdema
Other changes, such as tearing, discharge, et c. are also noted.
Risk Assessment
Risk refers to the chance of an adverse effect to a toxicant.
In order to properly estimate the risk or chance of toxicity, the hazard
must first be identified. Then the exposure level or dose must be
estimated (is exposure to a drop or 55 gallons more likely?) and the frequency
of potential exposure must also be estimated.
These estimates, along with the adverse effects known to occur at various
doses, are used to establish the Minimum Exposure Limit (MLE) or Threshold
Limit Value (TLV). These estimates for allowable exposure are often
difficult to make, especially with carcinogens that may require only exposure
to one molecule on a single occasion to cause cancer.
In estimating risks, assumptions must be made on certain points based
upon animal studies, prior exposure to similar compounds or involving similar
work situations, and epidemiological data. Any of these assumptions
could be false or erroneous. Therefore, to minimise the potential
harm, the most conservative estimate (the one least likely to cause toxic
exposure) is used as the model to establish a safe level of use.
This is done by choosing the worst case scenario as the minimum for safety
(in other words, if one model predicts only 1 person out of a hundred will
be exposed and suffer ill-effects while a second model predicts that 10
people will be exposed and suffer ill-effects, the second model is chosen,
thus limiting the use of the compound, since the second model predicts
a higher rate of toxicity).
Risk-Benefit Analysis
In most instances the risk of exposure is weighed against the potential
benefit to society or industry to determine whether the estimated risk
is worth the benefit of potential exposure. In almost all cases involving
potential human or environmental exposure, a risk-benefit analysis has
been performed to determine the relative value of using the compound.
Risk Management
Risk management is comprised of two separate and distinct activities.
The first is pro-active in nature and is designed to reduce the risk of
exposure to a particular toxicant. By ensuring proper handling, transport,
and use of a toxicant, the risk for exposure is minimised. Thus the
potential risk is managed. Reactive risk management includes those
procedures that are in place that must be followed after exposure as taken
place, to minimise the harm that may occur as a result of the exposure.
In any case involving potentially toxic compounds, absolute safety can
not be guaranteed.
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