Frequently Asked Questions
Here are some of the frequently asked toxicology questions together with the answers that I have compiled from toxicology training sessions and programs that have been held during 2012 – 2018.
I hope that you find these useful and if you have any toxicological questions you would like answered please contact me.If you are interested in learning more about different aspects of toxicology please take a look at my training course scheduled for 2016 and my recently launched Toxicology Training Online web-based course. Details are can be found at the top of the page.
NOAEL and LOAEL Related Toxicology Questions
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.
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.
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) )
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]
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.
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. It is not the same as a NOAEL.
In general NOAELs and LOAELs will be derived from animal studies.
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
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
“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