Dear Julie,

Assessing Acute Toxicity

Scientists use animal tests called LD50 (L-D-fifty) studies to assess acute toxicity. These studies determine the amount of a substance that will kill half the test animals in 14 days. This amount is called the LD50--Lethal Dose for 50% of the animals.

LD50 is stated in milligrams per kilogram (mg/kg): milligram of chemical per kilogram of body weight. * The lower the LD50-the lower the lethal dose-the more toxic the substance.

The term LC50-Lethal Concentration-is used to measure the toxicity of gases. The LC50 is stated in milligram of chemical per liter (or cubic meter) of air.

Example: A reported "rat oral LD50 of 50 mg/kg" means that half of the rats that ingested a dose of 50 milligrams of the substance per kilogram of body weight died within 14 days.

LD50 values are unknown for humans, but animal LD50 values can be used to estimate lethal amounts for humans.

Non-Carcinogenic Assessment

Non-carcinogenic chronic toxicity is assessed by studies to determine the smallest dose that causes any detectable effect. Scientists assess non-carcinogenic chronic toxicity by administering varying amounts of a substance (dose) to laboratory animals and noting the effects (responses), if any, at each dose. Essentially, the scientists look for the smallest dose that causes any detectable effect. This smallest dose is called the Lowest Observable Effect Level (LOEL). *

To conduct these dose-response studies, scientists:

Administer different small doses of a substance to several groups of test animals every day over a lifetime. Periodically examine and finally autopsy the animals to determine if any effects have occurred. The effects may be:damage to an organ,

behavioral modifications, change in the level of an essentialbody chemical.

Determine the smallest dose at which an effect occurs--the Lowest Observable Effect Level (LOEL). LOEL is measured in milligrams (mg) of substance per kilogram (kg) of body weight, or in parts per million (ppm) of substance in food.

In addition to LOEL, the term LOAEL (Lowest Observable Adverse Effect Level) is sometimes used. The term LOAEL implies a judgement that the effect is adverse. A LOEL refers to any effect and may or may not be judged to be adverse.

Careful examination of the definition of both terms reveals that there is no correlation between the terms LD50 and LOEL.

http://ruby.fgcu.edu/Courses/Twimberley/IDS3920/chap3.html

Hoping this will be helpful,

Rafik

Thank you very much. I understand that the two terms indicate a very different tipe of toxicity (different targets, mechanisms etc...). However, a "numerical" correlation might exist and it would be useful to know it in case only LD50 is present in litterature and we need to use the LOEL for Permitted Dose Exposure calculation (PDE) - with all the safety factors of the case. I think I will investigate this better to see if previous studies show LD50 values that are actually suggestive of LOEL.

These two different terms represent different parameters. LD50 on one side represent the lethal dose that killed at least 50% of test animals while LOEL represent lowest dose that can generate observable adverse effect. 

Similarly LD50 in industrial pharmacy is a major factor to choose a product for cleaning validation. While LOEL gives the limit which should be prohibited to reach the next products. 

Dear Julie,

There is no correlation between LD50 and LOAEL, since these values describe quite different toxicological endpoints. There are compounds with relative low accute toxicity values while their LOAELs in repeated dose studies are orders of magnitude lower. Additionally considerably more endpoints are examined in repeated doses studies. The only correlation which exists might be that the LOAEL is always lower than the LD50.

Best regards

Thomas

I agree with postings explaining the differences and submit there is a simple example of the difference: H2O has an LD50, resulting in water intoxication, hyponatremia, and other metabolic derangements.  There is no analogous LOEL or LOAEL with this substance, and in fact is essential to the function of most organisms. 

Thank you all for your explanations! I was curious to know this because I needed to make a calculation to find a PDE of a substance that had only an LD50. For PDE calculations the formula considers LOEL or NOEL values. However, in cases where no data is available and only LD50 is available the so called NOEL can be calculated following the following equation (APIC, 2014): NOEL = (LD50 x BW)/2000. I just would like to verify the rationale behind this.

Dear Julie,

Assuming a BW of 200 g, this would end up at an NOEL of one tenth of the LD50. This makes no sense at all. I had compounds in development with NOAELs of LD50 / 1000 and less, depending on the study dcuration.

Best regards

Thomas

For such guidelines bw is considered 70 kg, an average human adult. N

I think the rationale is pretty simple - if you don't have the data for the LOEL, you can make a very rough calculation of it using the LD50 as above, but this is just an estimate. As such, this doesn't imply any correlation between the LOEL and LD50 - it's just using the LD50 as a substitute in the calculation, because the LD50 is easier and cheaper to determine. In reality, this calculation is often going to be very different from what you would determine if you quantified the LOEL experimentally. Because drugs can often bind to multiple receptors/enzymes in the body, the receptor which is responsible for the LD50 can be completely different to that which is responsible for the LOEL. A good example is thalidomide, where the sedative effect which is responsible for the LD50 is mediated through an entirely different mechanism than the teratogenicity (birth defects).

Is there a database of LD50, ED50, TD50, LOEL and NOEL etc for each medication sold in the United States? I'm interested in these numbers for all the prototype drugs. 

Thanks

I think this is a valid question. Of course LD50 and LOEL are based on different mechanisms or toxicities, however, in risk assessment when nothing else except for a LD50 is available, then it is desirable to estimate a LOEL using that LD50. That being said, I have not seen anything in literature related to LD50-LOEL correlation or extrapolation. However, there are several studies that looked that at LD50-chronic NOAEL extrapolation. Most of them suggest a factor of >10,000 to estimate a chronic NOAEL using a LD50.

As such there is no thumb rule for the LD50-chronic NOAEL extrapolation. Most of them suggest a factor of >10,000 to estimate a chronic NOAEL using a LD50 is based on the literature and oneself judgement .

I appreciate the interest in "rules of thumb" for LD50 relationship to NOAEL, however the core of this discussion is the nature and mechanism of toxicity which seems to be ignored. If for instance, a compound is a suicide substrate and knocks out a specific enzyme or vital biochemical cascade, these are related more closely. If the compound causes cancer at low exposure levels but also affects an unrelated biochemical process at high levels, then the >10,000 rule may be relevant or useful. It is likely that this generalization is not really useful in scientific circles. Defining LD50 and NOAEL specifically are important in an environment where numerous chemical entities are being released without detailed toxicological vetting.

I appreciate the interest in "rules of thumb" for LD50 relationship to NOAEL, however the core of this discussion is the nature and mechanism of toxicity which seems to be ignored. If for instance, a compound is a suicide substrate and knocks out a specific enzyme or vital biochemical cascade, these are related more closely. If the compound causes cancer at low exposure levels but also affects an unrelated biochemical process at high levels, then the >10,000 rule may be relevant or useful.

It is likely that this generalization is not really useful in scientific circles. Defining LD50 and NOAEL specifically are important in an environment where numerous chemical entities are being released without detailed toxicological vetting.

Julie Rambaldi Hi, you mentioned an equation from published paper (APIC, 2014): NOEL = (LD50 x BW)/2000. Could you please offer the detailed citation of this paper？ I'm also very interested in the possible correlation between LD50 and LOEL. Thanks a lot.

Hi Jianquin Qian, the reference is a document from ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE (APIC): GUIDANCE ON ASPECTS OF CLEANING VALIDATION IN ACTIVE PHARMACEUTICAL INGREDIENT PLANTS