Toxicity of insulin due to phenol and metacresol

[Nnora]

Hi everyone,
I was wondering if anyone here was thinking about toxic substances present in insulin formulations. For example, Novorapid contains 1.5 mg/ml of phenol and 1.72 mg/ml of metacresol. Both of these substances are very toxic, and for someone who is injecting 20 units of insulin per day, means also 300 ppm of phenol per day and 344 ppm of m-cresol.
Here is the study that was dealing with cell death induced with these substances.
http://www.sciencedirect.com/science/article/pii/S2214750014001541
On the other hand, I understand that for the purification step, in the production of insulin, phenol is used to separate protein from DNA, but there must be an alternative which is safer.

 

[tim2000s]

No and I really don't think it is worth it. You have a choice. You take insulin, which requires a preservative and sterilisation agent or you die. The damage being caused by these insulins doesn't seem to me, at least, to be something I would consider to be a problem when compared to the alternative. Note that they didn't include any of the other insulins that all contain this stuff.

Like I said, you have a choice. You take it or you die. It's fairly stark really!

 

[Nnora]

I agree with you, for a consumer there is not much of a choice offered on the shell. But the market pull can do miracles and drive technology changes. Why not demand safer products? From a process technologist point of view, I would consider different production methods, and as a formulation scientist I would strive for less toxic preservative alternatives, which do exist. The problem is, as in many spheres of life, unawareness.

 

[urbanracer]

Hi everyone,
I was wondering if anyone here was thinking about toxic substances present in insulin formulations. For example, Novorapid contains 1.5 mg/ml of phenol and 1.72 mg/ml of metacresol. Both of these substances are very toxic, and for someone who is injecting 20 units of insulin per day, means also 300 ppm of phenol per day and 344 ppm of m-cresol.
Here is the study that was dealing with cell death induced with these substances.
http://www.sciencedirect.com/science/article/pii/S2214750014001541
On the other hand, I understand that for the purification step, in the production of insulin, phenol is used to separate protein from DNA, but there must be an alternative which is safer.

For me, the numbers don't add up:-

ISO Constants:-
1 ppm = 1mg/L
1L = 1000mL
1mL = 100 units (insulin)

By calculation:-
20units of insulin is therefore 0.2mL
300ppm = 300mg/L (So you'd need to inject a litre of insulin to reach this level at the stated concentration).

Therefore:-
To inject a litre of insulin in increments 20units would require (1000/0.2 mL) 5000 injections.

I don't see this as a daily regime but I'm happy to be proved wrong......................

 

[ann34+]

Hi everyone,
I was wondering if anyone here was thinking about toxic substances present in insulin formulations. For example, Novorapid contains 1.5 mg/ml of phenol and 1.72 mg/ml of metacresol. Both of these substances are very toxic, and for someone who is injecting 20 units of insulin per day, means also 300 ppm of phenol per day and 344 ppm of m-cresol.
Here is the study that was dealing with cell death induced with these substances.
http://www.sciencedirect.com/science/article/pii/S2214750014001541
On the other hand, I understand that for the purification step, in the production of insulin, phenol is used to separate protein from DNA, but there must be an alternative which is safer.

thanks, very interesting science direct reference, especially the reference to pump infusion site problems, my insulin contains slightly different proportions - 0.06% phenol, and 0.16% m-cresol - it would be good to have other preservatives.

 

[tim2000s]

The bigger question is whether it is really causing any issues. While this research establishes that the preservatives and sterility providers are vaguely toxic, it doesn't look at the in situ conditions and the question as to whether it is toxicity or healing that causes a requirement to change sets.

 

[Dark Horse]

Not sure why you are quoting ppm (parts per million)? If Novorapid has 100 units per ml then 20 units will be contained in 0.2 mls. At the concentrations quoted, this volume will contain a total of 0.3 mg (300 micrograms) of phenol and 0.344mg (344 micrograms) of metacresol.

Insulin would be dangerous if contaminated with pathogens so it is better to have permitted levels of preservatives and follow the advice of the article quoted, "To minimize acute skin complications caused by phenol/m-cresol accumulation, a frequent change of infusion sets and rotation of the infusion site is recommended."

 

[ann34+]

The bigger question is whether it is really causing any issues. While this research establishes that the preservatives and sterility providers are vaguely toxic, it doesn't look at the in situ conditions and the question as to whether it is toxicity or healing that causes a requirement to change sets.

Agree, but at present we just dont know - the sciencedirect article references a whole lot of interesting studies, and by following the references in some of these I have realised how much more complex the infusion site issues in particular may be, especially over the long term, and how much they are being studied.

 

[nmr1991]

its like i read somewhere bananas contrain minute traces of cyanide and uranium which are naturally produced but pose no harm to the body unless you have like 50 at once at the point it becomes any close to harmful, believe what you want to believe

 

[tim2000s]

Agree, but at present we just dont know - the sciencedirect article references a whole lot of interesting studies, and by following the references in some of these I have realised how much more complex the infusion site issues in particular may be, especially over the long term, and how much they are being studied.

And given the percentage of T1s using CSII compared with the number using injections, it will remain a low priority. As it stands, this is a first world problem with limited value in large amounts of investigation. I'm sure it will continue but I don't expect fast progress.

 

[Jaylee]

Hi everyone,
I was wondering if anyone here was thinking about toxic substances present in insulin formulations. For example, Novorapid contains 1.5 mg/ml of phenol and 1.72 mg/ml of metacresol. Both of these substances are very toxic, and for someone who is injecting 20 units of insulin per day, means also 300 ppm of phenol per day and 344 ppm of m-cresol.
Here is the study that was dealing with cell death induced with these substances.
http://www.sciencedirect.com/science/article/pii/S2214750014001541
On the other hand, I understand that for the purification step, in the production of insulin, phenol is used to separate protein from DNA, but there must be an alternative which is safer.

Yep, many years ago. (In my late teens early 20's) it had occurred to me about what else is in the stuff while using "insulatard" at the time.. There was this "suspension fluid" where it had to be mixed a little like a spray paint can? There was a little glas ball in the vial..

But as stated earlier. What is the alternative.?!
Cheers for bringing this up though. My Doctor at the time just looked at me blank when I enquired on my therory. (No internet back then.)

 

[Robinredbreast]

Hi everyone,
I was wondering if anyone here was thinking about toxic substances present in insulin formulations. For example, Novorapid contains 1.5 mg/ml of phenol and 1.72 mg/ml of metacresol. Both of these substances are very toxic, and for someone who is injecting 20 units of insulin per day, means also 300 ppm of phenol per day and 344 ppm of m-cresol.
Here is the study that was dealing with cell death induced with these substances.
http://www.sciencedirect.com/science/article/pii/S2214750014001541
On the other hand, I understand that for the purification step, in the production of insulin, phenol is used to separate protein from DNA, but there must be an alternative which is safer.

Maybe in the future there will be an alternative. I would imagine the use of a 'pump' attached in some way to the persons body would of seemed extreme with possible complications many years ago and like most medications there can be side affects. As some have said, it does keep us alive and many type 1's have had the condition for decades, 50 years + and have lived a long time.

 

[Nnora]

For me, the numbers don't add up:-

ISO Constants:-
1 ppm = 1mg/L
1L = 1000mL
1mL = 100 units (insulin)

Calculation:
concentration of phenol in Novorapid is
1,5 mg/ml so in 1 ml (100 units) you have 1,5 mg of phenol or 1500 mg/l which is 1500 ppm, so in 100 units (1ml) there is 1500 ppm of phenol. Seems a lot.

 

[Nnora]

I am sure that phenol m-cresol are not the only preservatives available and they are probably used for cheap separation od protein from the DNA of the species used to make it (bacteria). For the rest, I can do some research. Some other resin is a possibility, like this one used in lab
https://advansta.com/products/RapidClean/

 

[tim2000s]

I am sure that phenol m-cresol are not the only preservatives available and they are probably used for cheap separation od protein from the DNA of the species used to make it (bacteria). For the rest, I can do some research. Some other resin is a possibility, like this one used in lab
https://advansta.com/products/RapidClean/

The question is whether it removes the proteins in a way that they can be reused in insulin in an effective manner.

 

[Nnora]

And given the percentage of T1s using CSII compared with the number using injections, it will remain a low priority. As it stands, this is a first world problem with limited value in large amounts of investigation. I'm sure it will continue but I don't expect fast progress.

I was searching for an insulin that has less phenol and/or m-cresol and I found none, regardles of application method (injection, CSII, IV). No wonder why ghe risk of cancer in diabetic patients is incerased.

 

[yingtong]

I've been using insulin for 54 years with no adverse effects,in fact it's kept me alive and I intend to keep using it,so I will take my chances.

 

[tim2000s]

I was searching for an insulin that has less phenol and/or m-cresol and I found none, regardles of application method (injection, CSII, IV). No wonder why ghe risk of cancer in diabetic patients is incerased.

Are you a mother of a newly diagnosed child? I'm not saying you are looking for reasons for something but you seem to be focussing on a very narrow subset of the reasons for a correlation between cancer and Type 1Diabetes. There's a major discussion here: http://care.diabetesjournals.org/content/33/7/1674.long on this topic and you have to also considered the changes in th e body caused by the loss of the beta cells plus the side effects of basic hyperinsulinemia due to exogenous insulin. It's not as straightforward as a single ingredient in an insulin analogue.

 

[urbanracer]

Calculation:
concentration of phenol in Novorapid is
1,5 mg/ml so in 1 ml (100 units) you have 1,5 mg of phenol or 1500 mg/l which is 1500 ppm, so in 100 units (1ml) there is 1500 ppm of phenol. Seems a lot.

No there isn't, you are confusing the SI units.
There may be 1500 mg/L but there are not 1500ppm in 100 units (1ml) since it's only 1/1000th of a litre. ((1ppm = 1mg/L))

And in the OP you stated the phenol concentration is 300ppm and now you are claiming it's 1500ppm ?

 

[tim2000s]

@urbanracer The details of Insulin Aspart state 1.5mg/ml, as mentioned in the FDA briefing on the product. http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4254b_13_04_KP InsulinAspartFDAlabel102005.pdf

However, I personally inject <50u of Novorapid daily, so I'd be experiencing the effect of <0.75mg of phenol, which is well under what are considered to be "safe" levels.

On that point, it's also worth noting that in the statement in the science direct paper, phenol was noted to cause cellular death when the levels exceeded 1.2mg/ml/24 hours.

It's also worth noting that the levels at which adipocytes were damaged (with Phenol) was at 2.3mg/ml/24 hours and upwards. Again, this is a high amount of insulin.

In other words, what I take away from the study is that larger amounts of insulin, which increase the phenol and m-cresol concentration in cells, cause greater cell damage. That ignores that high levels of exogenous insulin also cause other metabolic issues that probably far outweigh the cell damage concerns.

The key point of the study appears to be to identify whether it is the Phenol/m-Cresol components of insulin as well as the invasive nature of the cannula that results in tissue damage, or whether it is just the latter. As the study says, more investigation is needed from both a control and testing inhibitors that may make a difference perspective.

As a footnote, I note that even when not continually infusing insulin through an injection port, there is still a similar level of irritation, so I question whether the hypothesis that it is heavily attributable to stability enhancers in the insulin is accurate.

In the meantime, I intend to continue to take insulin and stay alive.