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NOAEL and LOAEL Related Toxicology Questions
Q. What is an LD50?
A. The LD50 or lethal dose 50% is the dose which causes death (lethality) in 50% of the test population. If exposure is by either the oral or dermal route, it is expressed as the amount of test substance per unit body weight (mg/kg (bw)).
If inhalation is the chosen exposure route then it is expressed as LC50 (lethal concentration, 50%) and the units are usually mg/m3. That is, milligrams of test substance per cubic metre of air.
Q. What is between NOAEL AND LOAEL I mean what can we observe?
A. The No Observed Adverse Effect Level is experimentally derived and indicates the highest dose where no adverse effects are seen under the conditions of the study. The Lowest Observed Adverse Effect Level is the lowest dose used in a study that causes an adverse effect. This means that in the same study the NOAEL would be the dose level that precedes the LOAEL.
For example, if the dose levels used in a repeated dose study are 0, 50, 100,150 mg/kg (bw) and adverse effects were noted at 100 mg/kg (bw).
The NOAEL would be 50 mg/kg (bw) and the LOAEL would be 100 mg/kg (bw).
Observations would be made for each dose level but nothing would be seen between the doses as by definition the NOAEL is the highest dose where no adverse effects occur and the LOAEL is the lowest dose where adverse effects first occur. In other words, there are no other doses in between the two of these.
Q. Is NOAEL calculated or measured?
A. The NOAEL (No observed adverse effect level) is an experimentally derived value and is specific to the conditions and type of study undertaken. However, it should be noted that there are some circumstances where it is not possible to derive a NOAEL.
For example, If adverse effects were reported at the lowest dose used in the study then the NOAEL would not be derived and the LOAEL would be equivalent to the lowest dose (i.e. LOAEL = 50 mg/kg (bw) )
Q. How do you handle requests for NOAEL when there is only LD50 available?
A. This is a commonly asked question. Unfortunately, it is not possible to extrapolate from LD50 to NOAEL. This is because an LD50 value is related to lethality arising from acute exposure, whereas the NOAEL is the highest dose administered under the conditions of a longer-term study, where no adverse effects are reported. [See also question below]
Q. Is it possible to use acute toxicity data to predict likely chronic effects?
A. Acute toxicity is concerned with the adverse effects which arise from single or multiple exposures to a relatively large amount of chemical within a 24 hour period. Chronic toxicity is related to the adverse effects as a result of repeated exposure to smaller amounts of chemical (compared to acute toxicity) over a much longer time period (months or years!)
It is not possible to predict likely chronic effects from acute toxicity data and vice versa as they are very different with respect to how they occur. That is, the target organs involved, the mechanism of action and of course the resulting adverse effect.
Q. What is the difference between DNEL and NOAEL?
A. The NOAEL is an experimentally derived value which indicates the highest dose, under the conditions of the study where no adverse effects are reported. A DNEL (Derived No Effect Level) is defined as the level of exposure above which humans should not be exposed. This value is used in risk characterisation.
Q. For NOAEL and LOAEL is the observed effect is on animal or humans?
A. In general NOAELs and LOAELs will be derived from animal studies.
Q. What are the differences between an adverse effect and a non-adverse effect?
A. An adverse effect is defined by WHO/IPCS as “a change in the morphology, physiology, growth, development, reproduction, or lifespan of an organism, system, or (sub) population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress, or an increase in susceptibility to other influences.” However, something which is non-adverse would typically relate to those effects which overall do not compromise the overall well being of the organism and its ability to thrive. This could include transient or minor changes at the biochemical level and adaptive responses (as is the case with the liver).
Local, Systemic, Acute and Chronic Effects
Q. Are local/systemic effects the same as acute /chronic effects?
A. Local effects occur at the site of contact. Examples of this include accidental splashing with irritants such as dilute acids and alkalis. Systemic effects occur when the substance has been absorbed into the body and bloodstream.
Acute and chronic effects arise as a result of systemic exposure. Therefore local effects are not the same as acute and chronic effects, but both acute and chronic effects are in fact systemic effects.
Q. What about multiple toxins in the body synergism and antagonism?
A. Mixture effects are a very difficult area of toxicology and one which is difficult to predict. In terms of definitions, Synergistic effects are where the combined effect is greater than the sum of the individual effects if exposure occurred to each of the substances alone. That is 1+ 1 >> 2. For example carbon tetrachloride and alcohol. Antagonism is where the combined effect is less than the sum of the individual effects of the two substances if exposure occurred individually. That is 3+3 < 6. For example, ethanol can antagonise the effects of methanol.
Q. Can inhalation also result in absorption?
A. Yes, assuming that the chemical is able to penetrate to the lower part of the lung (alveoli) and into the bloodstream.
Toxicology Testing Related Questions
Q. In case a substance is corrosive to skin and we waive the EU irritation study, do we have to classify as eye irritant?
A. If a substance is known to be corrosive to the skin (for example due to pH), it would not be necessary to undertake an eye irritation/corrosion study. Such substances would automatically be classified as causing severe eye damage.
Q. Is Allergic Contact Dermatitis the same as Irritant Contact Dermatitis?
A. No it is not. Allergic contact dermatitis is a systemic effect involving the immune system whereas irritant contact dermatitis is a local effect which does not involve the immune system. However, clinically the symptoms are very difficult to distinguish.
Q. In vitro testing and animal testing, what is the difference?
A. In vitro means “in glass” and such testing involves, for example, the use of cultured cells in petri dishes. In vivo testing involves the use of living organisms, such as rats and mice.
Q. How do you test for reproductive toxicity in vitro or which species?
A. There is currently no validated alternative study (in vitro) that can fully replace a reproductive toxicity study. Reproductive toxicity studies are typically conducted in rats or mice.
Q. What is the difference between one-generation and a two-generation reproductive toxicity study?
A. A one-generation reproductive toxicity study involves dosing of the male and female prior to and during mating until conception. The female is then dosed throughout pregnancy and weaning of the offspring, where the study is terminated. This means that the one generation reproductive toxicity study does not look at potential effects which may occur throughout the whole of the reproductive cycle; such as effects on the reproductive capacity of the offspring.
A two-generation reproductive toxicity study is similar in principle to the one generation reproductive toxicity study except dosing continues throughout the reproductive cycle (past weaning) and investigates the potential adverse effects on the reproductive capacity of the offspring.
Q. What is the difference between a chronic toxicity study and a carcinogenicity study?
A. The aim of a chronic toxicity study is to investigate the effects of daily exposure to the chemical substance for the greater part of the lifespan. Information including the types of adverse effect (both local and systemic), target organs, dose-response, etc. will be investigated. In some cases, tumours may be reported but this is not the main objective of a chronic toxicity study.
The main objective of a carcinogenicity study, however, is to investigate the carcinogenic potential of a test substance. Other systemic effects (non-carcinogenic) may also be reported in such a study.
Q. What is a Target Organ?
A. A target organ is an organ, such as liver or kidney where adverse effects are seen as a result of chemical exposure. For example, the target organ of carbon tetrachloride is the liver.
Q. Is the EOGRTS test already accepted for REACH?
A. “The REACH annexes VIII, IX and X have been amended with the inclusion of the extended one-generation reproductive toxicity study (EOGRTS, EU B.56, OECD TG 443). EOGRTS is now the information required for reproductive toxicity in REACH instead of the two-generation reproductive toxicity study (EU B.35, OECD TG 416).
The updated annexes entered into force on the 13 March 2015. ECHA has updated its guidance on reproductive toxicity to reflect the regulatory changes.”
Go to the ECHA website at http://echa.europa.eu/documents/10162/13632/information_requirements_r7a_en.pdf