Thanks Nagaraju.

I am looking for the direct correlation between LD50 values and permitted daily exposure of particular substance.

Because, all of the above are the standard theory not for the safe and the effective prescription. All of the above referring to the theory  “creating the death curve = LD50 and then the AUC -Are Under Curve- without avoiding the Dubois formula OK ?? Mr. Nagaraju.!!  For that reason we would like to inform you that we have completed a protocol referring to the Post-Market Evaluation advance Studies of any medical cpd. All the indications are covered by using advanced biochemical markers especially for safety and efficacy of drugs.

We are looking forward to co-working with you and hope that we could work out a respectively satisfactory arrangement.

Awaiting the favor of your reply at your earliest convenience and thanking you in advance.

Yours sincerely,

Kyriakos Pispirigos PhD.

Specialist in Clinical Biochemistry

ex. Associate Prof. & Researcher

at C.Y.N.Y. New York, U.S.A.

Director of  Clinical Biochemistry Research Center

There is no such formula relationship with LD50.There is a rule of thumb that a safe upper limit for an acute dose is 10% of LD50. This is not always true, since some substances have a wide variance. But for most therapeutic compounds it is.

What you are talking about is similar to the concept of Maximum Allowable Daily Level (MADL), which is legally defined in California as the NOEL/1,000. MADL, and PDE are based on NOEL (No Observable Effect Level) or LOEL (Lowest Observable Effect Level) values. Then, you take some fraction of that. One needs to keep in mind that rats and mice tend to have significantly higher NOEL and LOEL values than humans. Rabbits are a better experimental animal for NOEL and LOEL.

Also, the PDE for a drug excipient, for instance, needs to be calculated based on reasonable total exposure.

So, for methanol, the NOEL in rabbits is 2000mg/kg-day. The standard 58 kg human female would have a NOEL of 116,000 mg/day. MADL is the NOEL divided by 1,000. So, that would be 116 mg/day orally.

But for pharmaceutical use, an oral PDE of 30 mg/day of ethanol for the 58 kg woman is generally used. That's about 1/4 the MADL.

Why is that? First, methanol should not really be in the drug in the first place because it has no role. Second, drugs are given to people who are often in highly compromised condition. For instance, if a patient has hepatitis, or cirrhosis of the liver, their ability to detoxify methanol may be compromised. Third, PDE is from one source, and drug injection or oral ingestion is usually very good at delivery into the system. MADL is from all sources. 

For all these reasons, PDE is usually much lower than the environmental measure which is MADL.

But, those are just guidelines. What really matters is what the blood level is from an exposure route, what the background blood level is, whether there is a background, and where observable effects start to appear. For instance, background in blood for methanol is 1-2 mg/liter. If you add 1 mg/liter to that, does it really matter? Not likely. 

You also need to account for reasonable estimates of mixtures which may not have linear effects. For instance, the same dose of methanol delivered as part of an ethanol dose does not act the same as a dose of  pure methanol. Since people drink ethanol, this needs to be taken into account.

So there isn't one answer. PDE should be based on literature evidence, laboratory tests, and reasonable estimates of what makes sense. PDE for a drug formula excipient should be minimized, but if it can't be done without great effort, then one can to ask - What is the risk versus benefit for this formula? For instance, let's say you could get the methanol level down to 30 mg/day for the dose of your drug. But let's say that really can't be done without multiplying the drug cost by 50 times? Let's say that this extra step means that 2% of the drug you manufactured survives the process intact?  Then, depending on the country it is to be sold in, perhaps it might be acceptable to allow 100mg/day for the 58 kg woman. But, in many cases, when companies really try, they find out that maybe there is a way to clean it up and still keep the price of the drug at an acceptable level.

If this is for a drug formula (and PDE suggests that drug formula is what you care about) you should be able to look up things like solvents and excipients in schedules from the FDA or EMA. India may have a similar agency.

In the end, it is a judgement call that is made. Weigh the evidence, weigh the benefit. 

Hmm. You got me curious. It is sometimes done that 10% of LD50 is used as the LOEL, and divided by 1,000 when there wasn't a NOEL available. So, that would be approximately, LD50/40,000.  But I would be careful. If there isn't LOEL or NOEL data, why is that? Perhaps some experiments are needed.

Dear all,

I would like to know the rationale behind "There is a rule of thumb that a safe upper limit for an acute dose is 10% of LD50". Are there any references that support this "rule"? Thank you in advance.

Nothing I can cite, no. But I haven't found a contradiction yet, although it may exist. I learned it from a professor in grad school as a good place to start if no experimental data existed. There are compounds where the safe acute dose is much higher fractions. That could be an interesting survey to do over different classes of materials and worth a publication. If there is an exception, I would hazard a guess it might be found in some venom components perhaps.

How can we use the LD50 values for calculations of Prescription Drug Event ?          In order to calculate Prescription new events due to the LD50 values you have to know the precision of the death curve and the variety of Lethal Dose occur and Post-Market side effects reports if agree ? , all these came out of many years of preclinical experiance with preclinical studies, PK?             

Dear Girish

IT is a job function of toxicologist to determine PDE. Determination of PDE is done using a formula but it is not just formula. Toxicologist needs to understand the profile of molecule to apply correct parameters to selected critical toxicity effect.

This is an expert job. In most cases it would not be appropriate to use LD50 to determine PDE. There are reasons, PDE is for life long administration whereas LD50 is an acute toxicity parameter. Hence lot of care is required if LD50 is used to determine PDE.

Please contact me if you need any more information 

Toxicology

Toxicology is the study of the adverse effects of xenobiotics

Professionals that study and perform toxicology-related work are called toxicologists, however, their specific job titles may vary.  

Toxicologists are scientists that study the health effects of exposure to substances and the mechanisms associated with exposure to those substances. 

A toxicology professional may work for industry (such as a pharmaceutical company, or chemical company), the government, or colleges and universities, toxicology labs.

Toxicology specialties

Occupational Toxicology - establish occupational exposure limits (OELs), determine potential adverse health effects, and author material safety data sheets.

Partner with industrial hygiene professionals to prevent occupational exposures to active pharmaceutical ingredients (API), or chemical substances.

Environmental Toxicology: study how chemical pollution effects people; work for an environmental consulting firm, a regulatory agency, or other governmental agency.

Pharmaceutical Toxicology: determine efficacy, mechanism of actions, and potential adverse health effects of API (Research or Manufacturing), OEL, PDE

Forensic Toxicology:  Forensic toxicology professionals establish the cause of death or identify clues that can solve a crime.

Toxicologist in Pharmaceutical Industry

A Pharmaceutical toxicology a multi-talented professional - background of chemistry, biology, Physics, Pharmacy, Pharmacology, Toxicology, Industrial Pharmacy, occupational Toxicology

Preventing occupational exposure to potent compounds posing hazards to employees.

Prevent over-exposure to these substances.

Conduct risk assessments for compounds early in development and place compounds in potent compound categorization or control banding schemes.

Develop occupational exposure limits and participate in potent compound safety training in order to prevent over-exposure to potent compounds.

Classify compounds into the control banding scheme. Control banding is a method used to assess the hazards of chemicals and manage exposures to these chemicals. It is a process that matches a control measure to a band of hazards or exposures.

 Toxicologist in Pharmaceutical Industry

Perform literature reviews and prepare supporting documentation of levels of excipients and residual solvents for acceptance by the Regulatory Agencies

Perform reproductive hazard evaluations, in which the toxicologist conducts a review of the reproductive hazards of the workplace and provide the client with a detailed report discussing potential hazards and potential steps to prevent exposure to these hazards.

Prevent exposure to potent compounds by providing categorization of compounds and by setting occupational exposure limits.

The role of Pharmaceutical toxicologist in preventing exposure to potent compounds is imperative for the health of the employees and the productivity of the company

Pharmaceutical Toxicologist in Industry

Identify Hazards

Perform Risk assessment of exposure to patient because of carryover

Define Risk of hazard

Review of literature

Review of toxicological profile

Define PDE

FAQ/ Myths regarding PDEs, ADEs, and OELs

Is there some magical unicorn database or computer program available on the Internet that will provide both the OEL and ADE for free?

Sorry there is None, so you can stop wasting your time searching for one right now.

There’s several reason why this “free database” doesn’t exist. Why?

Two groups of professionals establish OELs and ADEs, either toxicology professionals internal to a pharmaceutical company or expert consultants. No reason that they will work for free

Researching and preparing the necessary documentation to support an OEL/ADE takes time and effort and requires professional accumen

Please don’t discount the value of an informational product or service just because it’s not a hard tangible item (like a tablet press);

Finally, PDE, ADE, or OEL has the potential to impact multi-million dollar (or rupee) decisions. Do you really want to base that decision on some unsupported, “free” number that you found on the Internet? Get your numbers from credible sources.

FAQ/ Myths regarding PDEs, ADEs, and OELs

Two OELs or ADEs for the same compound, the lower number must be correct or a better

False. A lower number might be right – or it might be wrong.

There is need to critically review the OEL/ADE monograph documentation to make that determination (this is why having just a “number” is a worthless and dangerous practice)

Lower OEL/ADE numbers might exist because someone selected a difference point of departure, or more commonly, the person calculating the OEL or ADE was not confident in their own technical abilities so they overcompensated by using larger uncertainty factors than what is necessary.

It could also occur because an OEL/ADE for the compound was established when the compound was early in development and uncertainty was high. Remember, unnecessarily low OELs or ADEs cost a pharmaceutical company money, in terms of unnecessary engineering controls, elaborate work practices, or elaborate cleaning practices. The documentation for an OEL or ADE must present a reasonable scientific argument to support the number.

FAQ/ Myths regarding PDEs, ADEs, and OELs

Once an OEL or ADE is established for a compound, it will never change. 

Nope, not true. As a compound moves through the pharmaceutical development process, the OEL/ADE are likely to change.

In addition, sometimes adverse health effects appear that did not show up in clinical trials. Therefore, the OEL and ADE must be revised.

FAQ/ Myths regarding PDEs, ADEs, and OELs

OELs and ADEs are a bright line between safe and unsafe. 

OELs and ADEs are NOT precise numbers.

They are protective, but not precise. OELs and ADEs are an extrapolation of a known dose (NOAEL, NOEL, lowest daily dose, etc.) to an unknown dose that is believe to be protective over a Life long period of exposure

A difference between an OEL of 200 vs. 233 ug/m3 is a meaningless rounding difference

Unfortunately, regulatory agencies don’t help us out much here with their practices of saying that if you’re just barely over an OEL, you’re in violation

FAQ/ Myths regarding PDEs, ADEs, and OELs

The equations for both OELs and ADEs look pretty simply, I can do these calculations myself.

You can try, but unless you’re an expert with the advanced education, training and experience, you will have a tough time defending yourself to regulators or an attorney when you get it wrong.

In addition, the EMA is requiring a CV summary of the person preparing the PDE.

Good luck defending your number if you don’t have the relevant training, education, and experience on your CV.

FAQ/ Myths regarding PDEs, ADEs, and OELs

An OEL that is presented on a material safety data sheet is always correct.

Nope. Many are wrong. Some are really wrong. In addition, the SDS may be a legacy version and never get revised with a new number once new data is available.

Furthermore, it is a common practice of one company copying, probably incorrect information from one SDS to the next SDS, resulting in dozens of safety data sheets for APIs with incorrect information.

Vet out your sources!

FAQ/ Myths regarding PDEs, ADEs, and OELs

All I need is the OEL and ADE number. Give me the number for free.

A number without documentation and cited references is not credible or the approach is not verifiable and won’t survive the rigor of a regulatory inspection.

You won’t get an OEL or ADE monograph for free.

FAQ/ Myths regarding PDEs, ADEs, and OELs

I’ve taken a webinar, seminar, workshop, or bootcamp on potent compound safety and OEL/ADE setting, doesn’t that make me qualified to do this work myself?

Not going to happen.

There are NO overnight experts in any field. Taking webinars, seminars, workshops and bootcamps are all good things, but all they do is provide you with an awareness level of understanding, so you know the right questions to ask

If the SDS says that the OEL is “not available”, or that it is “not listed” by OSHA, ACGIH, or AIHA, then it must be “non-hazardous.”

“not available” does not equal “non-hazardous.” We have seen many SDSs that have the OEL listed as “not available” and these were for highly potent compounds

It is a nice discussion. After looking into this discussion. Now i have question. What will be the difference if we use NOAEL rather than NOEL to extrapolate LD50 to estmate safe thresh hold limits such as PDE/ADE/ADI

Trying to use the LD50 as the point of departure for determining the PDE/ADE is inadequate. If fact the EMA recently stated in their Q&A that it is not allowed.

Dear Dean Calhoun,

• As you may understand, in order to use successfully the values of the death curve results for the LD50 values, you should know to use the Dubois formula. In ours Laboratory we know very well to calculate the very unknown up to now Sub acute toxicity at the Post Market Level of any medical compound.
• All the indications are covered by using advanced biochemical markers especially for safety and efficacy of any compound.
• We are looking forward to co-working with you and hope that we could work out a respectively satisfactory arrangement.
• Awaiting the favor of your reply at your earliest convenience and thanking you in advance.
• Yours sincerely,
• Kyriakos Pispirigos PhD.
• Specialist in Clinical Biochemistry
• ex. Associate Prof. & Researcher
• at C.U.N.Y. New York, U.S.A.
• Director of Clinical Biochemistry Research Center

P.S.: If you have any questions then don't hesitate to get in touch,

KP/zp.

While your use of the Dubois formula may be useful, this is a regulatory issue and it would have to be "widely accepted" by the EMA for application to ADE/PDE. In their recent Q&A document on Implementation of Health-Based Exposure Limits, the EMA was pretty clear that the use of a LD50 was not an adequate PoD. See page 3, Q5. Additionally, the PoD used for PDE/ADE values is based on the critical effect, which could be any number of factors (reproductive, genotoxicity, carcinogenicity,, minimal therapeutic effect, etc.).