CYTOTOXICITY AND MUTAGENICITY IN HUMAN
TK6 LYMPHOBLASTOID CELLS EXPOSED IN VITRO TO
METHYLPHENIDATE

M. M. Carter, V. E. Walker, C. L. McCash and D. M. Walker. Cancer, LRRI,
Albuquerque, NM.

Methylphenidate(Ritalin, MPH) is a psycho-stimulant widely used for the treatment
of attention deficit/hyperactivity disorder (ADHD); however, a recent report
of cytogenetic effects in peripheral blood lymphocytes of children treated with
MPH for 3 months (El-Zein et al., Cancer Letters, in press) has raised concerns that
long-term exposure may pose a potential health risk. To investigate the mutagenic
effects of MPH in human cells in culture, a cloning assay was used to measure
cloning efficiencies (CEs) and mutant frequencies (MFs) in the hypoxanthine-guanine
phosphoribosyltransferase (HPRT) and thymidine kinase (TK) genes in TK6
cells exposed to MPH with/without human hepatic S9. TK6 cells exposed to 500
MPH µg/ml + S9 (n=6) for 3 days impeded cell growth with <2 rounds of replication
(compared with >3 in control cells) but was significantly mutagenic
(MF=8.65±2.12/million cells; control MF=5.39±1.91/million cells; p=0.01). In a
follow-up experiment, TK6 cells were exposed to 0, 250, or 500 µg MPH/ml,
with/without S9, for 4 days to acquire at least 3 rounds of cell replication for
treated cells. MPH treatments with or without S9 were cytotoxic relative to controls
(CE in treated cells were 50-56% of control values). Dose-related increases in
HPRT MFs were found in cells exposed to MPH in the presence of hepatic S9, but
not in its absence. Drug-induced MFs were significantly elevated in the 500 µg
MPH/ml + S9 group (n= 6, MF=13.86±7.12/million cells; p=0.007) but not the
250 µg MPH/ml + S9 group (n=5,MF=7.13±4.89/million cells) compared with
controls (n=7, MF=3.79±3.62/million cells). For both experiments, there was no
significant increase in TK MFs in any MPH treatment group, with/without S9.
These findings demonstrate that human hepatic enzymes have the capacity to convert
MPH to a mutagenic metabolite(s) that can induce mutations in exposed lymphocytes.
Further investigations of drugs used to treat children with ADHD are
needed to characterize the mode of action and potential risks of long-term exposure
to therapeutic agents such as MPH and d-amphetamine (Adderall) in children.

Oy. If you expose human tissue to just about anything in a test tube, it produces mutagenic effects. Milk, fruit juice, even tap water will screw with dna in a test tube.

Furthermore, this sentence:

These findings demonstrate that human hepatic enzymes have the capacity to convert
MPH to a mutagenic metabolite(s) that can induce mutations in exposed lymphocytes.
Does not seem to be supported by the evidence that is mentioned. What metabolites?

Also, note the tiny sample sizes and huge confidence intervals. Seeing these pretty much screws the pooch with regards to validity.

Look, if this was the only data you had to go on, then yeah, I might be worried. However, I am curious why no epidemiological survey has found an increased risk of cancer in methylphenidate patients as compared to the general public. This medication has been used since the 50's, millions of people have taken it, surely an epidemiological survey shouldn't be too difficult. If methylphenidate were carcinogenic, we ought to see an increased risk of cancer in patients taking methylphenidate once environmental and hereditary factors are controlled for. Given the number of patients taking the drug, and the length of time that the drug was on the market, such an effect would be blatantly obvious if it existed.

Finally, I'm also curious as to why they mention the need to look into other ADHD drugs. amphetamine and methylphenidate aren't really all that similar from a structural point of view, even though their method of action is similar. Even if methylphenidate were mutagenic or carcinogenic, it wouldn't really implicate amphetamine at all. Of course, I'm positive that there have already been mutagenicity studies of amphetamines, and as far as I know no mutagenicity or carcinogenicity has been found.

I will give you my interpretation of this article:

Based on this research methylphenidate does damage to genes after it has been converted by human enzymes into a mutagenic metabolite. Rats don't have these human enzymes so that explains why rats are immune to the mutagenic effects of methylphenidate.

So, IMO, this could be the end of all safe methylphenidate usage (for children anyway).

Oy. If you expose human tissue to just about anything in a test tube, it produces mutagenic effects. Milk, fruit juice, even tap water will screw with dna in a test tube.I'm not going to argue about this because I am looking for solutions, not trying to argue with you if ritalin is dangerous or not. I didn't said that ritalin was dangerous, just sharing this research.

Look, if this was the only data you had to go on, then yeah, I might be worried. However, I am curious why no epidemiological survey has found an increased risk of cancer in methylphenidate patients as compared to the general public. This medication has been used since the 50's, millions of people have taken it, surely an epidemiological survey shouldn't be too difficult. If methylphenidate were carcinogenic, we ought to see an increased risk of cancer in patients taking methylphenidate once environmental and hereditary factors are controlled for. Given the number of patients taking the drug, and the length of time that the drug was on the market, such an effect would be blatantly obvious if it existed.
It takes 2-10 years for leukemia to develop from exposure and most cancers develop 20-30 years after chemical exposure. I'm not sure, you should read Ruddon, Cancer biology. There it is explained.

No epidemiological survey has showed it because there are no epidemiologic survey conducted on the long term, I think. If you believe you found one then please share.

Hmmm, but that doesn't explain why we don't see this damage at the 250ug level.

Also, if this metabolite exists, it would be interesting to see it. Wouldn't it make more sense to first find the metabolite, then figure out how much of the metabolite will be present in vivo after taking an average dose, and then testing to see if those levels are mutagenic?

Finally, it still doesn't answer the question of the lack of epidemiological evidence linking methylphenidate to cancer.

I think that you are jumping to conclusions.

Finally, I'm also curious as to why they mention the need to look into other ADHD drugs. amphetamine and methylphenidate aren't really all that similar from a structural point of view, even though their method of action is similar. Even if methylphenidate were mutagenic or carcinogenic, it wouldn't really implicate amphetamine at all. Of course, I'm positive that there have already been mutagenicity studies of amphetamines, and as far as I know no mutagenicity or carcinogenicity has been found.
Yes, methamphetamine is genotoxic.

Li JH, Hu HC, Chen WB, Lin SK,
Genetic toxicity of methamphetamine in vitro and in human abusers.

Yes, life is hard for ADD'ers. But you have to move on.

Hmmm, but that doesn't explain why we don't see this damage at the 250ug level.I believe there is, but it isn't significant.

Also, if this metabolite exists, it would be interesting to see it. Wouldn't it make more sense to first find the metabolite, then figure out how much of the metabolite will be present in vivo after taking an average dose, and then testing to see if those levels are mutagenic?
Sounds difficult. Donno, I'm not a toxicologist. Maybe you should ask the authors.

The methylphenidate use really started between 1990 and 2000. In that period there was a great upsurge. So the consequences should be noticed between now and the future. So if this study proves true you see the negative health effects in the near future.

You can prevent cancer. Ever heard about Quercetin?

I did a scholar.google.com search for "methylphenidate AND Cancer" (but without the quotation marks, obviously).

The vast majority of the hits were for the use of methylphenidate in treating depression and fatigue in cancer patients, or using it to potentiate the action of painkillers. I did find one study showing that it caused a decrease in the incidence of mammary gland tumors in rats:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8603383&dopt=Citation

I finally added the term "epidemiological" to the search, in an effort to find such a study, and found a paper from California's dept of Health, in which they examined several possible carcinogens. Methylphenidate was examined and then dismissed as a possible cause of cancer. In this paper, they examined a long-term epidemiological survey which concluded:

In a screening study of participants in a health plan in Oakland, California, taking a wide range of prescription drugs
between 1969 and 1973 and followed up through 1984 (11-15 years later), 529 study subjects had received
methylphenidate HCl (Selby et al., 1989). No increased risk of cancer at any site was associated with
methylphenidate HCl exposure. Fifteen cases of cancer were observed (32.7 cases expected), resulting in a
standardized mortality ratio of 0.46 (negative association with p<0.002). Results were not adjusted for confounding
due to smoking or alcohol consumption because of limited data available for the cohort. Occurrence of cancer in the
general population was drawn from the California Resource for Cancer Epidemiology, the San Francisco Bay Area
tumor registry, and the hospital’s discharge abstracts.
http://www.oehha.ca.gov/prop65/pdf/Fb3sums.pdf

So we can take the word of two in vitro studies involving a handful of cases, or we can look at a long-term in vivo epidemiological study with 500 cases.

The study cited was:

Selby JV, Friedman GD, Fireman BH (1989). Screening prescription drugs for possible carcinogenicity: Eleven to
fifteen years of follow-up. Cancer Res 49:5736-5747.

I can be found here"

http://cancerres.aacrjournals.org/cgi/content/abstract/49/20/5736



Hmmmm.

The study of human methamphetamine users is confounded y the fact that illicitly produced methamphetamine often contains large amounts of impurities from poorly done synthesis which are known carcinogens.

Also, I'm not sure what

Yes, life is hard for ADD'ers. But you have to move on.
Is supposed to mean. Are you suggesting that people with ADD should stop using medications regardless of whether there is a link to cancer?

Yes, life is hard for ADD'ers. But you have to move on.As in suck it up, Buttercup? :eek:

Life without medication can indeed be a lot harder on an ADDer -- double the risk of drug abuse, increase in the number of traffic accidents, 3 x the prevalence of depression and anxiety compared to the general public, etc, so it makes sense to carefully evaluate the research before making blanket statements sure to inspire fear:
So, IMO, this could be the end of all safe methylphenidate usage (for children anyway).You admitted that you're not a toxocologist but yet your statement was absolute and went beyond what the authors of the study assert.

Scattered

You admitted that you're not a toxocologist but yet your statement was absolute and went beyond what the authors of the study assert.It's an opinion. You don't want to endanger children by exposing them to a (possible) mutagen.

Is supposed to mean. Are you suggesting that people with ADD should stop using medications regardless of whether there is a link to cancer?
No, never mind. You don't have to stop the meds even if there is a link. But you should do some chemoprevention I think. Discuss it with your doctor.

Selby JV, Friedman GD, Fireman BH (1989). Screening prescription drugs for possible carcinogenicity: Eleven to
fifteen years of follow-up. Cancer Res 49:5736-5747.
Let's hope this is enough safety.

Oh, here's the MSDS (Material Safety Data Sheet) for methylphenidate:

http://bulkpharm.mallinckrodt.com/_attachments/msds/MTHPN.htm

11. Toxicological Information


Oral rat LD50: 350 mg/kg; oral mouse LD50: 60 mg/kg; Investigated as a tumorigen.
--------\Cancer Lists\------------------------------------------------------
---NTP Carcinogen---
Ingredient Known Anticipated IARC Category
------------------------------------ ----- ----------- -------------
Methylphenidate hydrochloride No No None
(298-59-9)


And here are the MSDS for amphetamine (separated into amphetamine sulfate and amphetamine aspartate, oth of which are found in Adderall):

http://bulkpharm.mallinckrodt.com/_attachments/msds/APTAE.htm
http://bulkpharm.mallinckrodt.com/_attachments/msds/APTSE.htm

note that while they warn against using it during pregnancy due to possile risks to the fetus, amphetamines are also listed as eing non-carcinogenic:

11. Toxicological Information

Reproductive Toxicity:
The theraputic use of amphetamines during pregnancy may be associated with an increased risk of congenital malformations in the fetus. Reproductive studies in animals have suggested both an embryotoxic and a teratogenic potential when amphetamines were administered in high multiples of the human dose.
--------\Cancer Lists\------------------------------------------------------
---NTP Carcinogen---
Ingredient Known Anticipated IARC Category
------------------------------------ ----- ----------- -------------
Amphetamine Aspartate No No None

Arrrrg, the charts didn't line up right. Regardless, if you look on the pages, the charts have "no" listed under "known" and "anticipated," as well as "none" under the International Agency for Research on Cancer (part of the World Health Organization) category.

Just in case anyone is curious about the IARC's list of possible carcinogens:

http://users.westnet.gr/~aesclep/carcinog.htm

Yes hyperion. This information I already have. In fact I have looked up methylphenidate and related substances in the barkely carcinogenicity potency database. But... As rats are different from human, the rat carcinogenicity screening tests have less predictive power, I believe then the novel, human tests. To proof this I ask you to read this carefully the conclusion of the study I posted:

Quote:

These findings demonstrate that human hepatic enzymes have the capacity to convert
MPH to a mutagenic metabolite(s) that can induce mutations in exposed lymphocytes.

So MPH is mutagenic in humans, but not in rats, because rats lack these human hepatic enzymes. So that explains why rats did not develop tumors on methylphenidate when they tested methylphenidate on rats. Bacteria don't have human hepatic enzymes either, so when they tested methylphenidate with the AMES (bacteria) test they got negative.

I did some snooping around and found that most articles stating this possibility are all based on the one study in texas with the 12 kids.

But I did find a power point
http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4152s2_03_Jacobsen%20Kram.ppt (http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4152s2_03_Jacobsen%20Kram.ppt).
that explains that this study was investigated and that more studies are in process. The ppt also says that results should be available in a year.

I also found the original publication for the Texas study but could only access the abstract:

Cancer Lett. (javascript:AL_get(this, 'jour', 'Cancer Lett.');) 2005 Dec 18;230(2):284-91.Related Articles, (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=16297714&tool=ExternalSearch) Links (javascript:PopUpMenu2_Set(Menu16297714);)
http://www.ncbi.nlm.nih.gov/entrez/query/egifs/http:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?PrId=3048&uid=16297714&db=PubMed&url=http://linkinghub.elsevier.com/retrieve/pii/S0304-3835(05)00037-6)
Comment in:

Cancer Lett. 2005 Dec 18;230(2):292-4. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16019134&itool=pubmed_Abstract)
Cancer Lett. 2006 Jan 8;231(1):146-8. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16290920&itool=pubmed_Abstract)

Cytogenetic effects in children treated with methylphenidate.

El-Zein RA (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22El%2DZein+RA%22%5BAuthor%5D), Abdel-Rahman SZ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Abdel%2DRahman+SZ%22%5BAuthor%5D), Hay MJ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Hay+MJ%22%5BAuthor%5D), Lopez MS (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Lopez+MS%22%5BAuthor%5D), Bondy ML (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Bondy+ML%22%5BAuthor%5D), Morris DL (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Morris+DL%22%5BAuthor%5D), Legator MS (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Legator+MS%22%5BAuthor%5D).

Department of Epidemiology, Box 189, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

In recent years there has been a surge in methylphenidate (Ritalin) use for treatment of attention deficit/hyperactivity disorder (ADHD) in children. However, there is a paucity of information on whether this drug poses any potential health risks, such as mutagenicity or carcinogenicity, for humans. To address this issue, we investigated whether this central nervous system stimulant produces cytogenetic abnormalities in pediatric patients at therapeutic levels. In a population composed of twelve children treated with therapeutic doses of methylphenidate, we analyzed three cytogenetic endpoints in peripheral blood lymphocytes obtained before and three months after initiation of treatment with this drug. In all participants, treatment induced a significant 3, 4.3 and 2.4-fold increase in chromosome aberrations, sister chromatid exchanges and micronuclei frequencies, respectively (P=0.000 in all cases). These findings warrant further investigations of the possible health effects of methylphenidate in humans, especially in view of the well-documented relationship between elevated frequencies of chromosome aberrations and increased cancer risk.

Publication Types:

Clinical Trial (javascript:AL_get(this, 'ptyp', 'Clinical Trial');)

PMID: 16297714 [PubMed - indexed for MEDLINE] =================================

note: MGUS: Monoclonal gammopathy of undetermined significance. A benign condition in which there is a high level of a protein called M protein in the blood. Patients with MGUS are at an increased risk of developing cancer.
M proteins - Antibodies or parts of antibodies found in unusually large amounts in the blood or urine of people with multiple myeloma.
====================================

On the other hand...

Neuropsychopharmacology. (javascript:AL_get(this, 'jour', 'Neuropsychopharmacology.');) 2005 Jul;30(7):1374-82.Related Articles, (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15827573) Links (javascript:PopUpMenu2_Set(Menu15827573);)
http://www.ncbi.nlm.nih.gov/entrez/query/egifs/http:--www.nature.com-images-lo_npg.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/lofref.fcgi?PrId=3094&uid=15827573&db=PubMed&url=http://dx.doi.org/10.1038/sj.npp.1300718)
Dopamine transporter genotype and methylphenidate dose response in children with ADHD.

Stein MA (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Stein+MA%22%5BAuthor%5D), Waldman ID (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Waldman+ID%22%5BAuthor%5D), Sarampote CS (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Sarampote+CS%22%5BAuthor%5D), Seymour KE (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Seymour+KE%22%5BAuthor%5D), Robb AS (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Robb+AS%22%5BAuthor%5D), Conlon C (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Conlon+C%22%5BAuthor%5D), Kim SJ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Kim+SJ%22%5BAuthor%5D), Cook EH (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Cook+EH%22%5BAuthor%5D).

Department of Psychiatry, The University of Chicago, Chicago, IL 60637, USA. mstein@yoda.bsd.uchicago.edu

Stimulant medications, such as methylphenidate (MPH), are the most commonly used, effective treatment for ADHD. MPH acts primarily by inhibiting the dopamine transporter (DAT), a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals. We sought to evaluate the relationship between DAT1 3'-untranslated region (3'-UTR) variable number tandem repeats (VNTR) genotypes and dose response to MPH. Children with ADHD (n=47), ages 5-16 years (mean=9.02 years), underwent a 4-week, double-blinded, crossover trial with forced weekly dosage changes. Children were genotyped for the DAT1 VNTR and evaluated on placebo and three dosage levels of OROS MPH. Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms, impairment, and stimulant side effects each week. Children who were homozygous for the less common, 9-repeat DAT1 3'-UTR genotype displayed a distinct dose-response curve from that of the other genotype groups, with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments.

Publication Types:

Clinical Trial (javascript:AL_get(this, 'ptyp', 'Clinical Trial');)
Randomized Controlled Trial (javascript:AL_get(this, 'ptyp', 'Randomized Controlled Trial');)

PMID: 15827573 [PubMed - indexed for MEDLINE]

that explains that this study was investigated and that more studies are in process. The ppt also says that results should be available in a year. Yes this is the first study that is available.

And I know that if this proves true there may be tougher times coming. Especially for the children that got long term treatment with MPH. Children are even more vulnerable to mutagens then adults.

The original full study (2005):

http://psychrights.org/Drugs/cytogenetic-ritalin.pdf

Transcript from FDA (2005):

http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4152t2_Transcript.pdf

Selby JV, Friedman GD, Fireman BH (1989). Screening prescription drugs for possible carcinogenicity: Eleven to
fifteen years of follow-up. Cancer Res 49:5736-5747. Let's hope this is enough safety. Well, lemme explain what it means. They looked at a sample of 529 people who had taken methylphenidate, and then examined them 11-15 years later, which is right during the period in which you asserted that we would expect to see cancer popping up.

If we were to just take a random sample of 529 people off the street, and then performed a followup survey 11-15 years later, we would expect that roughly 32-33 of them would have developed cancer. So you could do an epidemiological study where you survey a group of people who all have a specific factor in common, and then do a followup after 11-15 years, and see how many developed cancer. If you took 529 cigarette smokers, you would likely find far more than 33 cases of cancer 11-15 years later. The fact that a sample of cigarette smokers will have much higher cancer rate is one of the major pieces of evidence that cigarette smoke causes cancer. If a given factor is carcinogenic, you would expect to see that a 529 person sample of people with that factor would result in far more than 32-33 cases of cancer after 11-15 years. If a factor causes that many cases or fewer, then it is not likely that this factor is carcinogenic.

One interesting thing about this study is that it is actually biased towards finding a higher incidence of cancer, because they don't control for other factors such as tobacco smoking. In other words, some of the people in the methylphenidate study may have been tobacco smokers, who would have a higher incidence of cancer and would therefore result in tobacco-caused cancer being inappropriately attributed to methylphenidate. However, even with this possible effect, the study still found that only 15 of the sujects developed cancer, which is far below the 32 cases that might be expected due to random chance, and far below what you would expect to see if methylphenidate were carcinogenic.

In other words, after conducting a long term survey to determine whether methylphenidate users had a higher rate of cancer, and even leaving in factors which might artificially inflate the rate of cancer, we still see that fewer methylphenidate users developed cancer than would be expected even due to random chance, and much fewer than would be expected if methylphenidate were carcinogenic. If methylphenidate were carcinogenic, we would expect to have seen far more incidents of cancer than were found.

11-15 years laterWell, according to what I have read in Ruddon, cancer biology it's actually 20-30 years (except for leukemia), but I donno if 11-15 years is enough, because I'm not a toxicologist. These studies, from what I have read, are very complicated, because not all cancer cases are reported, some people die from other causes and there are alot of other risk factors, such as smoking that may contribute to risk.

But it is reassuring ofcourse that these people did not all die at the end of the study.

Ehm hyperion, about the cigarette smokers. I actually compared the texan study with similar studies and I found out that 3 months of ritalin may actually equate to smoking 370 cigarettes a day. But I'm not sure.

Please read the study and compare it with other studies:

http://psychrights.org/Drugs/cytogenetic-ritalin.pdf (http://psychrights.org/Drugs/cytogenetic-ritalin.pdf)

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-AU-MsSAYVA-UUW-U-AACWCZWVEY-AACUAVBWEY-EWYZUUYCU- AU-U&_rdoc=4&_fmt=summary&_udi=B6V74-3YGDFD3-1C& amp;_coverDate=02%2F29%2F2000&_cdi=5832&_orig=search &_st=13&_sort=d&view=c&_acct=C000050221& _version=1&_urlVersion=0&_userid=10&md5=b9715b01 1b67af709b0b5044990ce626 (http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-AU-MsSAYVA-UUW-U-AACWCZWVEY-AACUAVBWEY-EWYZUUYCU-AU-U&_rdoc=4&_fmt=summary&_udi=B6V74-3YGDFD3-1C&_coverDate=02%2F29%2F2000&_cdi=5832&_orig=search&_st=13&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=b9715b011b67af709b0b5044990ce626)

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-AAU-MsSWYVW-UUA-U-AACWWWUBCW-AAVEYUAACW-EAYZYAUEW -AAU-U&_rdoc=27&_fmt=summary&_udi=B6V74-3V7C5G6- C&_coverDate=11%2F30%2F1998&_cdi=5832&_orig=sear ch&_st=13&_sort=d&view=c&_acct=C000050221&am p;_version=1&_urlVersion=0&_userid=10&md5=952bf9 beb4515cba3ee1ac15a303bf00 (http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-AAU-MsSWYVW-UUA-U-AACWWWUBCW-AAVEYUAACW-EAYZYAUEW-AAU-U&_rdoc=27&_fmt=summary&_udi=B6V74-3V7C5G6-C&_coverDate=11%2F30%2F1998&_cdi=5832&_orig=search&_st=13&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=952bf9beb4515cba3ee1ac15a303bf00)

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-AU-MsSAYVA-UUW-U-AACWCZWVEY-AACUAVBWEY-EWYZUUYCU- AU-U&_rdoc=1&_fmt=summary&_udi=B6WDM-4B4YWX8-3&a mp;_coverDate=01%2F31%2F2005&_cdi=6770&_orig=search& amp;_st=13&_sort=d&view=c&_acct=C000050221&_ version=1&_urlVersion=0&_userid=10&md5=6a07615e4 8522369d9d5eebbd25783e0 (http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-AU-MsSAYVA-UUW-U-AACWCZWVEY-AACUAVBWEY-EWYZUUYCU-AU-U&_rdoc=1&_fmt=summary&_udi=B6WDM-4B4YWX8-3&_coverDate=01%2F31%2F2005&_cdi=6770&_orig=search&_st=13&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=6a07615e48522369d9d5eebbd25783e0)

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-AW-MsSAYWA-UUA-U-AACWAAZEEY-AAVEZEDDEY-EAVYDVCVW- AW-U&_rdoc=9&_fmt=summary&_udi=B6WDS-45N4SM8-3&a mp;_coverDate=11%2F30%2F1997&_cdi=6774&_orig=search& amp;_st=13&_sort=d&view=c&_acct=C000050221&_ version=1&_urlVersion=0&_userid=10&md5=2cc754b55 ebcdcbecbfc9db5349232ce (http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-AW-MsSAYWA-UUA-U-AACWAAZEEY-AAVEZEDDEY-EAVYDVCVW-AW-U&_rdoc=9&_fmt=summary&_udi=B6WDS-45N4SM8-3&_coverDate=11%2F30%2F1997&_cdi=6774&_orig=search&_st=13&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=2cc754b55ebcdcbecbfc9db5349232ce)

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-AC-MsSWYVW-UUA-U-AACWABBWVB-AAVEDAVUVB-EACDAEAWZ- AC-U&_rdoc=10&_fmt=summary&_udi=B6T2C-47NV9CH-MG &_coverDate=12%2F31%2F1980&_cdi=4915&_orig=searc h&_st=13&_sort=d&view=c&_acct=C000050221& ;_version=1&_urlVersion=0&_userid=10&md5=165d7ec c38d0c425ac4a12a9d96aa004 (http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-AC-MsSWYVW-UUA-U-AACWABBWVB-AAVEDAVUVB-EACDAEAWZ-AC-U&_rdoc=10&_fmt=summary&_udi=B6T2C-47NV9CH-MG&_coverDate=12%2F31%2F1980&_cdi=4915&_orig=search&_st=13&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=165d7ecc38d0c425ac4a12a9d96aa004)

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-AY-MsSAYZA-UUA-U-AACWZAZZAE-AACUAEDVAE-EWEUWUDEB- AY-U&_rdoc=12&_fmt=summary&_udi=B6TCR-477XYBJ-19 P&_coverDate=11%2F30%2F1991&_cdi=5177&_orig=sear ch&_st=13&_sort=d&view=c&_acct=C000050221&am p;_version=1&_urlVersion=0&_userid=10&md5=3d5fe9 46d5b1fa2de3e4d9318b1757c2 (http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-AY-MsSAYZA-UUA-U-AACWZAZZAE-AACUAEDVAE-EWEUWUDEB-AY-U&_rdoc=12&_fmt=summary&_udi=B6TCR-477XYBJ-19P&_coverDate=11%2F30%2F1991&_cdi=5177&_orig=search&_st=13&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=3d5fe946d5b1fa2de3e4d9318b1757c2)

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-WY-MsSAYZW-UUW-U-AACWAAZYVY-AAVEZEDZVY-EAVYZCWUV- WY-U&_rdoc=25&_fmt=summary&_udi=B73FB-475JRXJ-2K &_coverDate=02%2F29%2F1988&_cdi=11494&_orig=sear ch&_st=13&_sort=d&view=c&_acct=C000050221&am p;_version=1&_urlVersion=0&_userid=10&md5=6d5f3a ccb840bd42f25bb83e8401bd87 (http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-WY-MsSAYZW-UUW-U-AACWAAZYVY-AAVEZEDZVY-EAVYZCWUV-WY-U&_rdoc=25&_fmt=summary&_udi=B73FB-475JRXJ-2K&_coverDate=02%2F29%2F1988&_cdi=11494&_orig=search&_st=13&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=6d5f3accb840bd42f25bb83e8401bd87)

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-A-MsSAYWA-UUA-U-AACWAACYZW-AAVEZEZZZW-EAVYUEAYB-A -U&_rdoc=1&_fmt=summary&_udi=B6T2D-4HF5KST-1& ;_coverDate=12%2F07%2F2005&_cdi=4916&_orig=search&am p;_st=13&_sort=d&view=c&_acct=C000050221&_ve rsion=1&_urlVersion=0&_userid=10&md5=29c5dc40c5e d5a159769dca19e1656b8 (http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-A-MsSAYWA-UUA-U-AACWAACYZW-AAVEZEZZZW-EAVYUEAYB-A-U&_rdoc=1&_fmt=summary&_udi=B6T2D-4HF5KST-1&_coverDate=12%2F07%2F2005&_cdi=4916&_orig=search&_st=13&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=29c5dc40c5ed5a159769dca19e1656b8)

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-WA-MsSAYWA-UUW-U-AACWCZWACV-AACUAVWECV-EWYCEZVEA- WA-U&_rdoc=12&_fmt=summary&_udi=B73FB-478NRS1-H& amp;_coverDate=07%2F31%2F1990&_cdi=11494&_orig=searc h&_st=13&_sort=d&view=c&_acct=C000050221& ;_version=1&_urlVersion=0&_userid=10&md5=d53769a 3b2c56e72334455938a04551a (http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-WA-MsSAYWA-UUW-U-AACWCZWACV-AACUAVWECV-EWYCEZVEA-WA-U&_rdoc=12&_fmt=summary&_udi=B73FB-478NRS1-H&_coverDate=07%2F31%2F1990&_cdi=11494&_orig=search&_st=13&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=d53769a3b2c56e72334455938a04551a)

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-AC-MsSWYWW-UUA-U-AACWYZYBYZ-AACUVVEAYZ-EBCYVAAWD- AC-U&_rdoc=7&_fmt=summary&_udi=B6T2D-3TMXYXN-6&a mp;_coverDate=09%2F01%2F1998&_cdi=4916&_orig=search& amp;_st=13&_sort=d&view=c&_acct=C000050221&_ version=1&_urlVersion=0&_userid=10&md5=276498864 e274931de9ad163095b1a37 (http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-AC-MsSWYWW-UUA-U-AACWYZYBYZ-AACUVVEAYZ-EBCYVAAWD- AC-U&_rdoc=7&_fmt=summary&_udi=B6T2D-3TMXYXN-6&a mp;_coverDate=09%2F01%2F1998&_cdi=4916&_orig=search& amp;_st=13&_sort=d&view=c&_acct=C000050221&_ version=1&_urlVersion=0&_userid=10&md5=276498864 e274931de9ad163095b1a37)

Compare the texan study with chernobyl:

http://www.sciencedirect.com/science?_ob=ArticleURL&_ase t=V-WA-A-W-A-MsSAYWA-UUA-U-AACWYDCZEV-AACUVCZVEV-EBZUCZZBW-A -U&_rdoc=1&_fmt=summary&_udi=B73H5-470NPJT-BJ&am p;am p;am p;_coverDate=09%2F26%2F1996&_cdi=11545&_orig=search& amp; amp; amp;_st=13&_sort=d&view=c&_acct=C000050221&_ version=1&_urlVersion=0&_userid=10&md5=538be2d92 6c462a7663acab9ac989d1b (http://www.sciencedirect.com/science?_ob=ArticleURL&_aset=V-WA-A-W-A-MsSAYWA-UUA-U-AACWYDCZEV-AACUVCZVEV-EBZUCZZBW-A-U&_rdoc=1&_fmt=summary&_udi=B73H5-470NPJT-BJ&_coverDate=09%2F26%2F1996&_cdi=11545&_orig=search&_st=13&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=538be2d926c462a7663acab9ac989d1b)

Abstract

The frequency of chromosomal aberrations was evaluated in more than 500 liquidators of the Chernobyl accident. The ‘sarcophagus’ builders and the dosimetrists showed the highest frequency of aberrations per 100 cells: 3.24 ± 0.25 and 3.11 ± 0.43. For Chernobyl Atomic Power Station staff members the mean frequencies of aberrations per 100 cells was 2.37 ± 0.20. The mean yields of aberrations in the other groups was between 1.31 and 1.47 per 100 cells.

When I search sciencedirect I got a feeling that we are going to make it into the guiness book of record.

Treatment with cyclophosphamide:

Therapeutically treated patients showed statistically higher baseline SCE frequencies than untreated control patients with a mean SCE/cell of 6.95 vs. 5.25, p < 0.016.

6.95 vs 5.25 SCE per cell

Ritalin treatment: 26.27 vs 6.09 SCE per cell

Quote:

smoking of one cigarette per day was associated with an increase of 0.054 SCEs/cell in SCE frequency.

So using ritalin for 3 months compares to smoking 370 cigarettes a day. (just a rough estimation ofcourse)

What is not understood is why there would not be alarm over using methylphenidate specifically for cancer patient use and other stuff?

The following also confuses: http://www.medsafe.govt.nz/profs/datasheet/m/Methylphenidatetab.htm

Pharmacokinetics

After oral administration the active substance (methylphenidate hydrochloride) is rapidly and almost completely absorbed. Owing to extensive first-pass metabolism its systemic availability is only 30% (11-51%) of the dose. Ingestion with food accelerates absorption, but has no effect on the amount absorbed. Peak plasma concentrations of about 40nmol/L (11ng/ml) are reached on average 1-2 hours after administration of 0.30 mg/kg. However, peak plasma concentrations vary markedly between patients. The area under the concentration-time curve (AUC), and the peak plasma concentrations, are proportional to the dose.

In blood, methylphenidate and its metabolites are distributed between plasma (57%) and erythrocytes (43%). Binding to plasma proteins of methylphenidate and its metabolites is low (10-33%). The apparent distribution volume is about 13.1L/kg.

Biotransformation of methylphenidate is rapid and extensive. Peak plasma concentrations of the main, de-esterified, metabolite, α-phenyl-2-piperidine acetic acid are attained about 2 hours after administration of methylphenidate, and are 30-50 times higher than those of the unchanged substance. The half-life of α-phenyl-2-piperidine acetic acid is about twice that of methylphenidate, and the mean systemic clearance is 0.17L/h/kg.

Only small amounts of hydroxylated metabolites (eg. hydroxymethylphenidate and hydroxyritalinic acid) are detectable. Therapeutic activity seems to be principally due to the parent compound.

Methylphenidate is eliminated from the plasma with a mean half-life of 2 hours. The apparent mean systemic clearance is 10L/h/kg. After oral administration, 78-97% of the dose is excreted in the urine and 1-3% in the faeces in the form of metabolites within 48-96 hours. Only small quantities (<1%) of unchanged methylphenidate appear in the urine. Most of the dose is excreted in the urine as α-phenyl-2-piperidine acetic acid (60-86%).

There are no apparent differences in the pharmacokinetic behaviour of methylphenidate between hyperactive children and normal adults. The elimination data indicate that in patients with normal renal function renal excretion of unchanged methylphenidate would hardly be diminished in the presence of impaired renal function. However, renal excretion of the metabolite α-phenyl-2-piperidine acetic acid may be reduced.

Use during pregnancy and lactation
There is no evidence of risk to the foetus, but experience during pregnancy is limited. In animal studies, Methylphenidate tablets did not affect reproductive performance or fertility and had no embryotoxic, fetotoxic or teratogenic effects at about 2-5 times the therapeutic dose in humans. Methylphenidate tablets should not be given to pregnant women unless the potential benefit outweighs the risk to the foetus. It is not known whether the active substance of Methylphenidate tablets and/or its metabolites pass into the breast milk. For safety reasons, breast-feeding mothers should not use Methylphenidate tablets.

Effects on ability to drive or use machines:

Because Methylphenidate tablets may cause dizziness and drowsiness, patients should be cautioned not to drive, operate machinery, or engage in other potentially dangerous activities.

Mutagenicity, Carcinogenicity and Toxicological Studies

In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas (a benign tumour) and, in males only, an increase in hepatoblastomas (a malignant tumour) at daily doses of approximately 60 mg/kg/day (about 30 times and 2.5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively). There is no overall increase in the number of malignant hepatic tumours. The mouse strain used is particularly sensitive to the development of hepatic tumours, and the significance of these results to humans is unknown.

Similar studies in F344 rats showed no evidence of carcinogenicity.

Sister chromatid exchange and chromosome aberrations were elevated in an in vitro test on cultured ovary cells of Chinese hamster but no mutagenic effects were observed in two further in vitro tests. (Ames reverse mutation test, mouse lymphoma forward mutation test). In an in vivo study of the effect of methylphenidate on mouse bone marrow cells (micronucleus test), in which doses up to 250 mg/kg were given, there was no evidence of clastogenic or aneugenic effects. The strain used for this in vivo assay was the B6C3F1 mouse, the same strain that produced a positive response in the mouse carcinogenicity study.

Comment:

The US Food and Drugs Administration examined data from the Surveillance, Epidemiology and End Results (SEER) database for the years 1973 to 1991 and found that the estimated incidence of hepatoblastoma in the general population was not greater than 1 in 10 million person years. On the basis of experience since marketing methylphenidate hydrochloride, there is no evidence that the incidence is higher in patients receiving methylphenidate hydrochloride.

Hyperion -- thanks for taking time to share this information and translate it into laymen's terms. Quiet reassuring!:)

Mutagenicity, Carcinogenicity and Toxicological Studies

In a lifetime carcinogenicity study carried out in B6C3F1 mice, methylphenidate caused an increase in hepatocellular adenomas (a benign tumour) and, in males only, an increase in hepatoblastomas (a malignant tumour) at daily doses of approximately 60 mg/kg/day (about 30 times and 2.5 times the maximum recommended human dose on a mg/kg and mg/m2 basis, respectively). There is no overall increase in the number of malignant hepatic tumours. The mouse strain used is particularly sensitive to the development of hepatic tumours, and the significance of these results to humans is unknown.

Similar studies in F344 rats showed no evidence of carcinogenicity.

Sister chromatid exchange and chromosome aberrations were elevated in an in vitro test on cultured ovary cells of Chinese hamster but no mutagenic effects were observed in two further in vitro tests. (Ames reverse mutation test, mouse lymphoma forward mutation test). In an in vivo study of the effect of methylphenidate on mouse bone marrow cells (micronucleus test), in which doses up to 250 mg/kg were given, there was no evidence of clastogenic or aneugenic effects. The strain used for this in vivo assay was the B6C3F1 mouse, the same strain that produced a positive response in the mouse carcinogenicity study.
I'll write it again for clarification.

Quote:

These findings demonstrate that human hepatic enzymes have the capacity to convert
MPH to a mutagenic metabolite(s) that can induce mutations in exposed lymphocytes.

So MPH is mutagenic in humans, but not in rats, because rats lack these human hepatic enzymes. So that explains why rats did not develop tumors on methylphenidate when they tested methylphenidate on rats. Bacteria don't have human hepatic enzymes either, so when they tested methylphenidate with the AMES (bacteria) test they got negative.

Now I'm going to bed.

The frequency of chromosomal aberrations was evaluated in more than 500 liquidators of the Chernobyl accident. The ‘sarcophagus’ builders and the dosimetrists showed the highest frequency of aberrations per 100 cells: 3.24 ± 0.25 and 3.11 ± 0.43. For Chernobyl Atomic Power Station staff members the mean frequencies of aberrations per 100 cells was 2.37 ± 0.20. The mean yields of aberrations in the other groups was between 1.31 and 1.47 per 100 cells.

When I search sciencedirect I got a feeling that we are going to make it into the guiness book of record.
no. One big thing that should jump out at you is that ADDers would be dropping like flies if you were correct. The fact that you don't see this ought to tell you something. In this situation, it turns out that you are comparing apples to oranges. You're comparing in-vivo tests of people exposed to environmental carcinogens, and in-vitro tests of cells which were injected with a chemical. If you took cells in a test tube and injected them with some of the materials found in Chernoyl, you'd see much higher levels than would be found in the workers.

This is what I meant when I said that in-vitro tests are often useless.

These findings demonstrate that human hepatic enzymes have the capacity to convert
MPH to a mutagenic metabolite(s) that can induce mutations in exposed lymphocytes.

So MPH is mutagenic in humans, but not in rats, because rats lack these human hepatic enzymes. So that explains why rats did not develop tumors on methylphenidate when they tested methylphenidate on rats. Bacteria don't have human hepatic enzymes either, so when they tested methylphenidate with the AMES (bacteria) test they got negative. Rats still have these S9 enzymes, so I don't know how this is relevent. Sure, they're not identical, but they're similar enough. Humans and rats aren't that different from a biological perspective. When looking at enzymes, even bacteria aren't that different, because metabolic enzymes are fairly well conserved during evolution. In fact, you have many bacterial metabolic enzymes in the mitochondria of your cells.

However, even if your assertion were correct, the human beings in the long-term survey that I quoted most certainly had human hepatic enzymes, so why didn't they develop cancer?

In other words, after conducting a long term survey to determine whether methylphenidate users had a higher rate of cancer, and even leaving in factors which might artificially inflate the rate of cancer, we still see that fewer methylphenidate users developed cancer than would be expected even due to random chance, and much fewer than would be expected if methylphenidate were carcinogenic. If methylphenidate were carcinogenic, we would expect to have seen far more incidents of cancer than were found.Now, this is definitely something to think about.

The methylphenidate use really started between 1990 and 2000. In that period there was a great upsurge. So the consequences should be noticed between now and the future. WRONG.

Methylpenidate has been in use since the 1930s. There may be more use today, but there are more people today. It's been used and studied widely enough in the last 70 years to produce the evidence that it is NOT "genotoxic".

I searched every academic database related to the biological science, including toxicology, and did not find this "study".

WHERE WAS IT PUBLISHED? OR RATHER, WAS IT PUBLISHED?

It's an opinion. You don't want to endanger children by exposing them to a (possible) mutagen. I'm offended by your suggestion that I would do such a thing.

I'm equally offended that you're here crying wolf about proven treatments and pushing quackery like "chemoprevention", which has been demonstrated repeatedly to have absolutely no effect on cancer rates.

In addition, you are outwardly suggesting that we ingest unregulated and potentially dangerous substances.

Just how are you helping people with this?

Cytogenetic effects in children treated with methylphenidate.

El-Zein RA (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22El%2DZein+RA%22%5BAuthor%5D), Abdel-Rahman SZ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Abdel%2DRahman+SZ%22%5BAuthor%5D), Hay MJ (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Hay+MJ%22%5BAuthor%5D), Lopez MS (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Lopez+MS%22%5BAuthor%5D), Bondy ML (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Bondy+ML%22%5BAuthor%5D), Morris DL (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Morris+DL%22%5BAuthor%5D), Legator MS (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&itool=PubMed_Abstract&term=%22Legator+MS%22%5BAuthor%5D).

Department of Epidemiology, Box 189, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

kvrrd,

I discussed the problems with this study EXTENSIVELY in another thread:

http://www.addforums.com/forums/showthread.php?p=274650

Okay, I've gotten through the thread & I have a few comments:



Thank you for being sane, Hyperion.
Steven d, I will wait patiently for a CITATION for the study in the OP. If this was published in a peer-reviewed academic journal, I'll probably be able to read and see for certain if there's something to worry about. If it was not, I can only conclude that it wouldn't pass peer review and is not valid - and "meeting abstracts" don't count.
Everyone else - despite a large number of studies, methylphenidate has never been indicated as increasing cancer risk. THAT'S THE BOTTOM LINE.

I'm still reeling from this statement:
"I found out that 3 months of ritalin may actually equate to smoking 370 cigarettes a day."
I know a respirologist who would disagree.

Steven d, I will wait patiently for a CITATION for the study in the OP. If this was published in a peer-reviewed academic journal, I'll probably be able to read and see for certain if there's something to worry about. If it was not, I can only conclude that it wouldn't pass peer review and is not valid - and "meeting abstracts" don't count.

I don't think this study has been published yet. From what I can tell, it is an abstract from a conference that was held back in March. It was probably from a presentation or poster session.

Now I'm going to bed.

Me too, I'm tired.

I'm still reeling from this statement:
"I found out that 3 months of ritalin may actually equate to smoking 370 cigarettes a day."
I know a respirologist who would disagree.And just what, exactly, is a "repirologist"????

There is absolutely NOTHING in that statement that can be supported by reality.

If reality isn't what you're interested in, by all means continue to make stuff up, but please don't scare people with it.

I don't think this study has been published yet. From what I can tell, it is an abstract from a conference that was held back in March. It was probably from a presentation or poster session.mmm hmmm. I easily found the abstract.

Until this study is described in detail in a peer-reviewed report, it's not even worth looking at.

And just what, exactly, is a "repirologist"????A respirologist, where I live, may be called a pulmonologist where you live? A respirologist is a physician with extra training in diseases of the lungs and respiratory tract.

However, even if your assertion were correct, the human beings in the long-term survey that I quoted most certainly had human hepatic enzymes, so why didn't they develop cancer?
I'm just speculating. But I'm no toxicologist and I can't answer your very detailed questions. Wow you ask me alot of questions... I donno, ask the authors of the study. I'm just stupid. According to Ruddon, Cancer Biology there is 20 years of time where the cells could transform into the malignant form. There is 20 years or so between the exposure and the tumor formation. Additionaly there are carcinogens that only initiate, but do not promote cancer creation and carcinogens that both act as an intiator and promotor. A promotor speeds up the process, shortening the 20 years latency period. Also, it is a possibility that cancer cells can also be destroyed by carcinogens (think about chemotherapy) because carcinogens may be toxic to cancerious cells. There is not enough information at the present to understand what the situation is.

To barbyma:

If you can't find the study you should ofcourse check with the authors. You check if they are good toxicologists or just amaturs. I don't believe the authors are just silly college students or scientologists. I believe they are real toxicologists.

https://www.toxicology.org/AI/FA/SOT_Toxicologist2006.pdf

In addition, you are outwardly suggesting that we ingest unregulated and potentially dangerous substances.What??? I'm not forcing you to do anything. I'm not a doctor and I never wrote that I was one. I would specifically tell you to do things in concert with your doctor. Potentially dangerous substances??? wow... Never thought about that...

If you can't find the study you should ofcourse check with the authors. You check if they are good toxicologists or just amaturs. I don't believe the authors are just silly college students or scientologists. I believe they are real toxicologists.It doesn't matter what their credentials are. This is not a published study, period.

The process of validation has not been done.

This process is the same for EVERYONE.

Unless/until it's published in a peer-reviewed journal, it's just chicken scratch. When/if published, it can be examined to see if it is more than just chicken scratch.



What??? I'm not forcing you to do anything. I'm not a doctor and I never wrote that I was one. I would specifically tell you to do things in concert with your doctor. Potentially dangerous substances??? wow... Never thought about that...Maybe you should.

I didn't say "forced". I said "suggested", and you've done so repeated in a tone that says you have all the answers to our problems (also suggesting we have problems).

I'm just speculating. But I'm no toxicologist and I can't answer your very detailed questions. Wow you ask me alot of questions...

If you have done your homework, and you are in the right, I predict this outcome for you. At best, after painting Barbyma into a corner, with study after blinding study refuting her position....months later on an unrelated thread she may subtly agree with you. :)

Now on the other hand, if you are dead wrong, your toast, Ghandied...and she will slowly incapacitate you as a child does by pulling the wings off of a fly. :p

Ya gotta ask yourself, is the hill I'm willing to die on? :soapbox:

I don't think this study has been published yet. From what I can tell, it is an abstract from a conference that was held back in March. It was probably from a presentation or poster session.
You check if they are good toxicologists or just amaturs. I don't believe the authors are just silly college students or scientologists. I believe they are real toxicologists.

It doesn't matter what their credentials are. This is not a published study, period.

The process of validation has not been done.

This process is the same for EVERYONE.

Unless/until it's published in a peer-reviewed journal, it's just chicken scratch. When/if published, it can be examined to see if it is more than just chicken scratch.

I figured I'd add a real-life anecdote to the discussion of conference papers vs. published academic papers:

A paper prepared for a conference is really not much more than a glorified term paper. I'm actually preparing a few papers (mostly regulatory overviews) for an upcoming medical conference. In these papers, I write about laws in various states which regulate particular areas of medical practice. However, it will be made clear at this conference that these papers are only meant to inform participants of the general state of affairs regarding public policy in these areas and aid them in making decisions regarding clinical practice guidelines. They are not peer-reviewed and would not constitute legal advice, although they are extensively researched.

If someone wanted actual legal advice on the subject, they would consult a lawyer or else they would consult the actual peer-reviewed academic papers which I cited.

I mention this because it is important to understand the difference between papers prepared for conferences and actual academic literature. Conference papers are meant merely to aid attendees in making policy. While we would all like them to be as accurate as possible, there really isn't much in the way of review, and what little review exists is entirely up to the organization organizing the conference (although in my case this is actually fairly extensive as evidenced by the scads of red ink all over my latest draft).

Also, in many conferences you will find that papers often seek to encourage one policy or another. For instance, while I personally try to explain the pros and cons of given options (because our docs' only real allegiance is to evidence, not policy), there are certainly conferences where papers may have a particular slant.

Anyways, the point is that all a paper must have to be presented at a conference is the agreement of the group or groups organizing the conference. If it comes from the group organizing the conference, then there's really not much outside review at all.

Papers which are published in academic journals, on the other hand, are required to undergo a (hopefully) rigorous peer-review process. I'm lucky in that policy analysts usually don't have to deal with this (since much of our work is basically the academic equivalent of an Op/Ed piece). For a journal to publish a paper, the authors must submit all of their evidence, methodology, analysis, etc. The paper is essentially considered, to use barb's term, "chicken scratch" until the authors can prove otherwise. There are no secrets allowed, no miracles, no "trust me" pleas involved. When experiments are involved, the "recipe" for the experiment must be provided so that it can be replicated.

Even once something is published, it is not considered "proven," but merely "evidence" which can be critiqued. In the scientific world, you don't get to preach to the choir, you have to defend your evidence every step of the way.

The reason for this is quite evident in this thread. You don't want people running off half-cocked flushing their meds down the drain every time someone cries "cancer." You don't want people to make policy decisions (my field) until they can look at well established research (barb's field). You want to make sure you confirm findings before you make decisions on them, because basing policy on bad evidence is actually often worse than failing to recognize an emerging threat.

If you want a good example of what kind of crap can occur when people make rash decisions based on crappy evidence, look at something that's going on in Britain right now. A few years ago, a researcher named Wakefield announced that he had found a link between a preservative in MMR vaccines and autism. As a result, thousands of parents foolishly avoided vaccinating their children, thus decimating the herd immunity that is necessary to prevent infectious diseases (people seem to forget what childhood was like before immunizations: nasty, brutish, and short). Today, Britain is seeing the worst measles outbreak in 20 years, and have seen the first child die of measles in 14 years. They may very well wind up with a minor epidemic on their hands. And the worst part? It turns out that Wakefield was secretly being paid by lawyers who wanted to file lawsuits against vaccine companies, and almost all of the patients in his "study" were litigants in the lawsuit, which he "forgot" to disclose in the study. Further studies have shown no link (autism rates continue to rise in several European countries that haven't used the preservative, thimerosal, in years), and Wakefield's own research appears to have been falsified to a large extent. He is now facing serious professional charges from the British equivalent of the AMA for several serious ethical breaches from this study.

This is what happens in the real world when people make foolish decisions based on unverified "research." Money gets wasted, people get sick, some of them die, and nothing gets solved. There are still plenty of autistic kids in Britain, but now there are also plenty of sick kids in Britain, including immunocompromised kids who couldn't be immunized who were dependent upon everyone else to do their part to maintain herd immunity. Many of these kids may not live to see their next birthday because this quack tried to make a few extra bucks from a lawsuit and thousands of parents were gullible enough to listen to him.

So if it seems like I'm being a little hard on you, Steven, it's because there can be very real consequences if people just blindly accept every claim without examining the evidence behind it. It might seem as though the whole scientific process is unfair or overly skeptical, but there are good reasons for it.

for more info on Wakefield, see here:

http://scienceblogs.com/insolence/2006/06/while_were_on_the_topic_of_aut.php#more

For more info on Wakefield, see here:

http://autismdiva.blogspot.com/2006/06/wakefieldism-vs-public-hea_115070450706095284.html

(warning: this link is a very long post...one difference between autistics and ADDers is that they tend to write very long, pedantic posts, and it can be difficult for us to read through them)

(I guess that could apply to me too...crap)

If you have done your homework, and you are in the right, I predict this outcome for you. At best, after painting Barbyma into a corner, with study after blinding study refuting her position....months later on an unrelated thread she may subtly agree with you. :)Subtly? :rolleyes: No need to paint me into a corner. If he was right it would be obvious and I'd say so flat out. I've done it here before.

I think you might be thinking you've changed my view with your excellent research on emotion regulation, but you'd be a little bit off the mark. :eyebrow: I was never in disagreement on your fundamental points. I may have backed off, but I didn't change my mind.

But, our debate isn't one that is anywhere near as black and white as this one. Yours was a sticky question and the answer changes with the definitions. You also had good reasons for your views on the matter (and researched and debated that view well), and my opinion on that matter is just opinion.

:soapbox: This one has a snowball's chance of swinging in his direction; the evidence is fairly unequivocal. :soapbox:



Now on the other hand, if you are dead wrong, your toast, Ghandied...and she will slowly incapacitate you as a child does by pulling the wings off of a fly. :pLove the analogy & your confidence is appreciated!:D

Anyways, the point is that all a paper must have to be presented at a conference is the agreement of the group or groups organizing the conference. If it comes from the group organizing the conference, then there's really not much outside review at all.
The majority of presentations at conferences in the fields of life sciences are either poster sessions or 15-minute presentations (via PowerPoint).

All that is submitted to the majority of conferences for review by the organizers is an abstract. It's often kept to less than 200 words.

Very few rejections occur.

Most people do not prepare a paper. Often you will be offered a handout that contains the same bare-bones info on the poster and a contact address. If it's a presentation, you won't even get that.



Papers which are published in academic journals, on the other hand, are required to undergo a (hopefully) rigorous peer-review process.
Yes, and if only that were enough!:p

The peer-review process serves mostly to reduce fraud. Unfortunately, poor methods still get through the process much more often than I'd like. A good 50% of what's published in academic journals is crap.

The big difference, IMO, between published and unpublished work is the amount of information. (your quote below) Because of this, we can examine the method & determine how strong the conclusions are.

There are no secrets allowed, no miracles, no "trust me" pleas involved. When experiments are involved, the "recipe" for the experiment must be provided so that it can be replicated.
Thank you, Hyperion, for that wonderful summary of the MMR scare and its ramifications. Very well said.

You can protect yourself against mutagenic effects by eating raspberries!

http://www.phytochemicals.info/phytochemicals/ellagic-acid.php

Ellagic acid works as an anit-mutagen.

http://www.jonbarron.org/images/raspberries.gif

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1628864&dopt=Abstract

You can protect yourself against mutagenic effects by eating raspberries!
ROTFLMAO!!!


I see that have no problem with rat studies when you think they support some miracle product.....

Intraperitoneal administration of ellagic acid to rats caused a decrease in total cytochrome P-450 levels and related activities as well as in cytosolic glutathione S-transferase activity. Finally, the possibility that the reported anticarcinogenic action of ellagic acid reflects nothing more than non-selective destruction of hepatic cytochromes P-450, and thus reduced chemical activation, is considered.

So it might reduce your risk of cancer, but it would drastically increase the risk of overdose from just about any drug or medication.

Steven d,

It pays to READ the stuff....

The very last line of the article is "It therefore seems
unlikely that dietary ellagic acid would be an effective
anticarcinogen in vivo."

non-selective destruction of hepatic cytochromes P-450But here is your human hepatic enzyme.

Well, if you don't like ellagic acid, you could also read about quercetin. It has works as an anti-mutagenic too.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=16012761&query_hl=3&itool=pubmed_docsum

I'm not telling you to do anything, as I am not a doctor. (btw. Raspberries are just food, not medicine)

Now I will probably get some kind of criticism post from barbyma telling me I did something wrong again. While in fact, I already know what she's going to post. Something like you are telling us to eat raspberries, but you are not a doctor. Or quercetin is much more dangerous then I think or anything like that. Or I can't advice you to eat a particular kind of fruit and that it isn't a medicine isn't relevant, fruits can be dangerous too. While in fact, I already knew that. But I got freedom of expression too. Should I ask barbyma everytime I write something if I am allowed to write it??? No. So I'll just write what I want to write. And then I get criticized for it. Then I read that I did this wrong or I did that wrong. It's always like that.

But here is your human hepatic enzyme
Errrm, not that I want to nitpick or anything, but the sentence above that, to which they were referring,

Intraperitoneal administration of ellagic acid to rats caused a decrease in total cytochrome P-450 levels
seemed fairly clear.

Rats also have P-450 enzymes. Many mammals have similar P-450 enzymes. Interestingly, while many of these enzymes are conserved in evolution (because they perform tasks necessary for survival), we do see variation in the total amounts of individual enzymes expressed even between individual humans. In general, most mammalian livers (and most tetrapod livers, really) will be fairly interchangeable. They may express different levels of different enzymes, and the speed with which they metabolize chemicals may change from species to species, but they're generally the same. Some species may lack an enzyme found in other species (which is why dogs can't eat chocolate), and very rarely you might see one species develop a novel enzyme (usually only a mild variation on a pre-existing one, though).

The liver is not an organ that can be altered drastically over a short period of time without killing the organism. Its function is simply too important, and it has no backup.

Now I will probably get some kind of criticism post from barbyma telling me I did something wrong again. While in fact, I already know what she's going to post. Something like you are telling us to eat raspberries, but you are not a doctor. Or quercetin is much more dangerous then I think or anything like that. Or I can't advice you to eat a particular kind of fruit and that it isn't a medicine isn't relevant, fruits can be dangerous too. While in fact, I already knew that. WRONGO! If you actually read my criticisms, you'd see that I NEVER criticize someone for their credentials (or lack thereof).

What I WILL criticize, however, is the evidence you present. Did you READ my last post? ALL I did was tell you what the study you posted CONCLUDED.

Here's what the study you cited in THIS post says: It says quercetin is not genotoxic to humans. It does NOT say quercetin is beneficial to humans in any way.....


But I got freedom of expression too. Should I ask barbyma everytime I write something if I am allowed to write it??? No. So I'll just write what I want to write. And then I get criticized for it. Then I read that I did this wrong or I did that wrong. It's always like that.I'm not responsible for the correctness or the quality of the information you post -- YOU are.

I don't criticize posts that provide accurate, relevant information that supports what the poster is trying to propose.

Well thank you hyperion for the information about the rats.

Thinking about this particular text I would say I have to add:

This is what happens in the real world when people make foolish decisions based on unverified "research." Money gets wasted, people get sick, some of them die, and nothing gets solved. There are still plenty of autistic kids in Britain, but now there are also plenty of sick kids in Britain, including immunocompromised kids who couldn't be immunized who were dependent upon everyone else to do their part to maintain herd immunity. Many of these kids may not live to see their next birthday because this quack tried to make a few extra bucks from a lawsuit and thousands of parents were gullible enough to listen to him.

So if it seems like I'm being a little hard on you, Steven, it's because there can be very real consequences if people just blindly accept every claim without examining the evidence behind it. It might seem as though the whole scientific process is unfair or overly skeptical, but there are good reasons for it.I don't completely agree about you on this. The reason is that the parents were very stupid enough not to go to the doctor for a consult before doing such a thing. Not getting a vaccin is something you should always consult a doctor for first. And they didn't obviously. So it is wrong to blame it all on wakefield. Ofcourse what Wakefield did was wrong. Still it happens and it shouldn't happen!!!

Another thing I would like to add is that the story could have been different. Should wakefield be a good scientist and he did found a connection between A and autism, thousands of autism cases could be easily prevented by acting on it. And the story was the other way around.
So what do you do about this? In this world we usually trust authority. If prof. or dr. X said this then do this... Why is this? Because we can't quite figure out ourselves what we should do. So we trust on authority.

Also I want to add. OFCOURSE I don't blindly accept every claim. I never made an absolute statement on ritalin. If I did, then I wrote something wrong. This is exactly why I am reading these researches. I would never advice anyone to do anything without consulting a doctor first.

And even if there were these negative health effects, that doesn't change a thing. We must examine how extreme the negative health effects are. If it is a minor thing, we act on it differently then if it is a major thing.

Something being carcinogenic does not equate to being dangerous. Alot of chemicals are carcinogenic. We must then asses how carcinogenic. Ofcourse I know this.

Here's what the study you cited in THIS post says: It says quercetin is not genotoxic to humans. It does NOT say quercetin is beneficial to humans in any way.....
OOOPS I provided the wrong link. (not)

Yes thank you for making it clear. (btw. It's not that I didn't knew this. I wanted to demonstrate the safety of quercetin for hyperion, because he seems to doubt the safety.)

Yes now I get to hear that I didn't succeeded in doing that.

The assumption that I want hyperion to use quercetin btw. is wrong. My intention was just to share information. Again, I am not a doctor and I can't advice anyone to use about anything.

I never made an absolute statement on ritalin. If I did, then I wrote something wrong. .
You may not intend to, but you come off sounding this way.



Based on this research methylphenidate does damage to genes after it has been converted by human enzymes into a mutagenic metabolite.

So MPH is mutagenic in humans, but not in rats, because rats lack these human hepatic enzymes

So using ritalin for 3 months compares to smoking 370 cigarettes a day. (just a rough estimation ofcourse)

You can protect yourself against mutagenic effects by eating raspberries! .

You may not intend to, but you come off sounding this way. Ok, that is really true. But I do understand and always understood that even if there is proof it is never 100% for sure. Ofcourse, I'm not that stupid. If I take this research as basis, then even if I don't work in the field I would not say that "ritalin is ...". But as every research is done we gain knowledge and we understand the entire picture. What I am waiting for is ofcourse new epidemiological data. I discussed EVERYTHING with my doctor too. And I would not recommend anyone to do something silly without doctors consent.

Steven d,

If you are as concerned with finding out what's correct, why do you keep arguing with people who are trying to tell you what this research says and means?

On the general subject of research, responsibility, and real-world effects, I'd like to look at two of your paragraphs, Steven.

I don't completely agree about you on this. The reason is that the parents were very stupid enough not to go to the doctor for a consult before doing such a thing. Not getting a vaccin is something you should always consult a doctor for first. And they didn't obviously. So it is wrong to blame it all on wakefield. Ofcourse what Wakefield did was wrong. Still it happens and it shouldn't happen!!!

On the one hand, you are correct that the parents involved had a certain responsibility to consult their doctors before making such a decision, and certainly their doctors would have told them "just get the damned vaccination." So yes, it may seem a bit unfair to blame Wakefield because of other people's stupidity. However, Wakefield was not some nut on a street corner, he was a well-respected researcher, which leads me to the second part of this point:


So what do you do about this? In this world we usually trust authority. If prof. or dr. X said this then do this... Why is this? Because we can't quite figure out ourselves what we should do. So we trust on authority.
What you're referring to here is something called "fiduciary responsibility." It is the legal concept that people who give advice based on a particular special expertise, such as lawyers or doctors or accountants, have a special obligation to ensure that their advice is both correct and ethically sound. This is because these experts are often advising people who lack the training in a particular subject to make a sound decision without their guidance. For instance, I'm a pretty smart guy, but if I needed to make a large financial transaction, I'd consult an accountant, because I am not an expert in that subject.

If you were to ask a friend for advice, you accept the possibility that they might give you bad advice. However, when someone offers their advice as an expert, they are in fact required to offer the best advice possible, because they are responsible, within reason, for the actions of those who follow their advice. Obviously, honest mistakes happen, but that does not appear to be what happened here. Part of fiduciary responsibility is the obligation to disclose potential conflicts of interest, as well as the obligation to conduct research in an ethical manner and an obligation to report your conclusions truthfully and accurately.

Andrew Wakefield failed to meet any of these obligations. There were multiple conflicts of interest (he failed to disclose that he had received funding from lawyers suing vaccine companies, that almost all of his subjects were parties in those lawsuits, and that Wakefield himself had patented a single-shot measles vaccine and stood to profit personally if MMR were discontinued). While we obviously must await the results of his upcoming hearings, it does appear as if Dr. Wakefield acted in an unprofessional manner, and that his results were influenced by ulterior motives, including personal profit.

As Dr. Wakefield conducted his research in such a shoddy manner, he should bear much responsibility for the actions of those who followed his advice. The parents who stupidly refused to vaccinate their children also deserve much blame. Especially because they are placing other children (those who cannot receive vaccines for medical reasons) at risk of serious illness or death. Trust me, if I had my way, they would all lose custody of their kids, and be forced to go three rounds in the ring with me without pads. However, Wakefield should have known, when he published the paper, that this result was possible. The fact that he put his own desire for profit (from his vaccine and a potential lawsuit settlement) above the interests of accurate research and public health is so far past inexcusable that frankly I consider it a travesty that he will not face prison time.

Similarly, El Zein and others who develop studies with deliberately small sample sizes, no controls, and other methodology designed to show a specific outcome, while deliberately ignoring epidemiological evidence (or even denigrating epidemiological sample sizes for being too small despite being 50 times larger than his own!) are committing a similar crime, and I use that word delierately. The fact that they refuse to submit these papers for publication implies that they know that their methodology is crap, and that they are more concerned with publicizing their "results" than they are with publishing their research. It implies that the results were more important to them than conducting accurate research.

It is curious that just as Wakefield conducted his studies in the hope of securing a major legal settlement against vaccine companies, these studies are being conducted as lawsuits are being filed against Novartis over Ritalin. It is curious that they would choose to perform the laoratory research on mutagenicity without first establishing epidemiological evidence showing higher rates of cancer. It appears as though these researchers may be attempting to show a specific outcome for the purposes of receiving a legal settlement. As with Wakefield, they should bear some responsibility if their research causes people to stop treatment or to avoid seeking treatment. Just as with the vaccine case, this is doubly disturbing because it will affect many children who cannot make their own medical decisions, which heightens the obligation to conduct and report research in an ethical and truthful manner.

Hyperion,
Nice comparison of the two situations.

As Dr. Wakefield conducted his research in such a shoddy manner, he should bear much responsibility for the actions of those who followed his advice. The parents who stupidly refused to vaccinate their children also deserve much blame. Especially because they are placing other children (those who cannot receive vaccines for medical reasons) at risk of serious illness or death. Trust me, if I had my way, they would all lose custody of their kids, and be forced to go three rounds in the ring with me without pads. However, Wakefield should have known, when he published the paper, that this result was possible. The fact that he put his own desire for profit (from his vaccine and a potential lawsuit settlement) above the interests of accurate research and public health is so far past inexcusable that frankly I consider it a travesty that he will not face prison time.Indeed it is scandalous. We trust them, they have the expertise. That is why we should never completely trust on one scientist. Reproduced work done by many scientists has more credibility. I know. And always discuss things with your doctor.

Similarly, El Zein and others who develop studies with deliberately small sample sizes, no controls, and other methodology designed to show a specific outcome, while deliberately ignoring epidemiological evidence (or even denigrating epidemiological sample sizes for being too small despite being 50 times larger than his own!) are committing a similar crime, and I use that word delierately. The fact that they refuse to submit these papers for publication implies that they know that their methodology is crap, and that they are more concerned with publicizing their "results" than they are with publishing their research. It implies that the results were more important to them than conducting accurate research.No, this I don't agree with you. El-zein was not the only author. Marvin Legator is coauthor. If you read about him, he was a legend (until his death). In fact, comparing him with wakefield is not possible and saying that their methodology is crap is completely wrong. In fact, you can't critisize their work unless you are a skilled and credible toxicologist yourself. Now... what's your real name dr...(Hyperion)???? Are you an expert in toxicology???

If you aren't then you are still allowed to critisize them, but your criticism lacks credibility. The same for me. I could one day said that professor X, expert in Y did this thing wrong. But I don't know anything about Y, so how can I accurate critisize, not even knowing what's it about.

What you can do is point to another expert that criticizes this study.

btw. IMO, that epidemiological study (500+ part.) was really crap. I seen epidemiological studies consisting of 4.000+ people, lasting 20 years.

http://www.pubmedcentral.gov/picrender.fcgi?artid=1242049&blobtype=pdf

And.. another reason is that the people participating did not ONLY use ritalin. The participants took other meds too. Which means that the sampling might have been wrong. What if they used alot of aspirin in this sample, that may also prevent cancer?

Hyperion,
Nice comparison of the two situations.Completely nutty comparison hyperion.

(Wakefield != Legator)

(Wakefield = Legator) = Stupitidy

If you are as concerned with finding out what's correct, why do you keep arguing with people who are trying to tell you what this research says and means?
I'm not arguing. I only have an opinion that is different from yours. But I would never tell you that my opinion was the "right" one, as I am not an expert. People see things differently and don't always agree. IMO, they don't have to agree.

No, this I don't agree with you. El-zein was not the only author. Marvin Legator is coauthor.
Wakefield had 13 co-authors for his paper (although interestingly, 10 have since retracted their support).

If you read about him, he was a legend (until his death).
Actually, Wakefield was also a very well respected researcher before this incident, which is why his paper was taken so seriously, and why this is such a tragedy. While I mentioned earlier that I wish he could receive jail time, he will see some punishment. His career is almost certainly over, he is virtually unemployable, and he may face some very stiff fines. In addition, he could face civil lawsuits from the parents of the kids who participated in the study (talk aout irony), as well as the parents of children who now are infected or have died from measles.

and saying that their methodology is crap is completely wrong
I don't know much about the methodology of the enzyme study mentioned here since it hasn't been published, but the first study, the pretest-posttest study, that one I can certainly say was crap. A tiny sample size and no controls. It's completely worthless. With such a small sample size, the validity and confidence intervals are worthless, there's simply too much random chance. With no controls, for all we know something else could be responsible. Maye they all lived next to a nuclear power plant, or they'd all had assloads of X-rays. Maye they'd just flown on a long intercontinental flight (which exposes a person to mild radiation levels). We don't know, because El-Zein neglected to include a control group to measure against. Without a control group, all you have is measurements changing over time. Sure, administration of methylphenidate was one thing that changed between sample 1 and sample 2, but unless you compare that to the naturally occuring changes that could be oserved in children of the same age group and geographic location who were not taking methylphenidate, you can't conclude that methylphenidate was the culprit.

Here's a good example of how the lack of controls can affect that. Let's say I take a group of 10 year old boys, and I measure their height. Then I have them all take methylphenidate every day for a year. Then I measure their height again, and it turns out that they have all grown taller. "Aha," I say, "methylphenidate doesn't stunt growth, it makes kids taller!" See, while it is technically true that each child acted as his own control, and while it is technically true that each child grew taller, there was no control group, so there is no way of knowing whether an external factor, in this case the normal growth spurts that kids get at that age, may have been responsible.

There isn't much information available about this second study, but the sample sizes are again miniscule. He uses even fewer samples, although at least he controls for a few different factors. The confidence intervals are astoundinly high, though:

Drug-induced MFs were significantly elevated in the 500 µg
MPH/ml + S9 group (n= 6, MF=13.86±7.12/million cells; p=0.007) but not the
250 µg MPH/ml + S9 group (n=5,MF=7.13±4.89/million cells) compared with
controls (n=7, MF=3.79±3.62/million cells).
If you were to plot these on a chart, you would notice that all of these values are actually within the same confidence interval. It is incredily disturbing to see a confidence interval which is well over 50% for the first two, and almost 100% for the third. Confidence intervals are those things you always see in political polling where they say "margin of error was plus or minus 3 percent." You want as low a confidence interval as possible, because it tells you what range the value could be. So let's look at the range of values possible here:

500ug methylphenidate:
6.74-30.98

250ug methylphenidate:
2.24-12.02

Control:
0.17-7.14



It is entirely possible for all three values to be clustered together around 6-7 MFs per million cells. Had they used a larger sample size, this would not be a prolem, but they chose ridiculously small sample sizes, and so we're left with enormous confidence intervals.

Furthermore, the addition of the hepatic enzymes skewed the results in a way that hadn't even occurred to me when I read it through the first time. They used TK6 cells, which are lymphoblast cells, they're present in the lymph nodes. Hepatic enzymes are found in liver cells (as the name implies). So you're taking liver enzymes and putting them in lymph node cells. They don't mention whether the control group also contained hepatic enzymes. If they did not, then you'd have to wonder whether the enzymes alone were responsible for the damage independent of the methylphenidate.

Even if the control cells did contain the enzyme, there are still issues: Even if we assume that there is some metabolite that is created when hepatic enzymes metabolize methylphenidate, there is still the question of how much of this metabolite will eventually reach the lymphocytes in the human body. It's a Rube Goldberg contraption here, methylphenidate enters the bloodstream, then passes through hepatic enzymes in the liver, then this metabolite reaches the lymphocytes.

As I mentioned efore, the small sample sizes and huge confidence intervals make me question whether there really are significant increases in MFs occuring. Even if they were ocurring, though, they'd need to identify the mysterious metabolite. They would then have to see what levels of this metabolite, if any, can cause MFs in these cells. Then they would have to see how much of this metaolite actually reaches the lymphocytes, since the enzymes which create the metabolite are not naturally present in those cells.

There is a lot more work that would need to be done in order to show even the slightest hint that these findings could cause problems. Given the lack of epidemiological evidence to show an increased risk, there is no reason to believe that further research will show it to cause cancer.

In fact, you can't critisize their work unless you are a skilled and credible toxicologist yourself.
Anyone who's taken a basic empirical research methods class can criticize these studies. This is the very basic stuff that every science field, even the "soft sciences" like sociology or political science, include as part of the undergrad education.

Now... what's your real name dr...(Hyperion)???? Are you an expert in toxicology???

A: I am not posting my real name, or any identifying information, on an internet message board that has thousands of members. In fact, Forum policy specifically forbids the exchange of personally identifying information.

B: I'm not a doctor, and have never presented myself as one. I am a healthcare/medical policy analyst. Policy analysts are people whose education is usually in political science/government/public policy, who then specialize in studying a particular field or industry. It requires a deep understanding of government regulation, macroeconomics, and the specifics of the particular field in which they choose to work. So for instance, a policy analyst wouldn't need to be able to diagnose a cancer patient and prescribe treatment, but he would need to know the treatments, treatment costs, prevalence rates, and mortality rates for different types of cancers, as well as how these might vary depending on when it is detected, and the different detection methods used. He'd need to know what people were most at risk for a particular type of cancer, and when and how often they should be tested. He'd need to be able to understand what chemicals might be carcinogenic for the purposes of regulating their use. Basically, policy analysts' jobs involve talking to the doctors, the lawyers, the legislators, the administrators, the patients and their advocacy groups, and then figuring out what everyone needs to be doing. So basically, while I'm not a toxicologist, this thread is right up my alley (although I don't do much work in oncology specifically).

What you can do is point to another expert that criticizes this study.

What about 7 of them? There is a response to El-Zein's study that was published at the same time, there's no abstract for it, but I might be able to see if I can find it Monday when I'm back at the office. The citation is:

Preston RJ, Kollins SH, Swanson JM, Greenhill LL, Wigal T, Elliott GR, Vitiello B.
Comments on 'Cytogenetic effects in children treated with methylphenidate' by El-Zein et al.
Cancer Lett. 2005 Dec 18;230(2):292-4. Epub 2005 Jul 12. No abstract available.
PMID: 16019134 [PubMed - indexed for MEDLINE]

btw. IMO, that epidemiological study (500+ part.) was really crap. I seen epidemiological studies consisting of 4.000+ people, lasting 20 years.
Ok, but 11-15 years is just about as good, certainly not much worse. As for the sample size, 529 isn't that bad for something like this, especially when they're only representing a population of 1-2 million. For comparison, a political poll for all voters in the country usually only uses a sample of 1,000 or so. Of course, that's a far more targeted sample, but the point is largely the same.

However, I see a little bit of cognitive dissonance here, since El-Zein's study used 12 people, and Carter's study involved betwen 5-7 samples depending on the group. Even if we assme that Carter's work, being in vitro, required a smaller size, why was 12 acceptale for El-Zein, but 529 wasn't acceptable for the other?


And.. another reason is that the people participating did not ONLY use ritalin. The participants took other meds too. Which means that the sampling might have been wrong. What if they used alot of aspirin in this sample, that may also prevent cancer?
Statistically, this should actually have increased their chances of contracting cancer. While there may be a few things that might help prevent it, the odds were actually greater that they might have smoked, or had unprotected sex (HPV can cause cancer), or worked in a profession that involved radiation exposure. It's actually unlikely for an epidemiological study, especially one involving cancer, to return a false negative. In cancer research, part of the problem is discounting false positives, where you might have several correlations, but only one of them means anything. With this epidemiological study, if methylphenidate had increased their risk of cancer, it would have shown in the study.

Completely nutty comparison hyperion.

(Wakefield != Legator)

(Wakefield = Legator) = Stupitidy
I don't know, I think it's fairly accurate. They're both controversial studies with the exact same ultra-low sample sizes, both of which contradicted mounds of epidemiological evidence and were both publicly criticized by many experts in the field, and both involved a well-established effective treatment for which there was a pre-existing lawsuit. The paralells are actually quite striking.

B: I'm not a doctor, and have never presented myself as one. I am a healthcare/medical policy analyst. Policy analysts are people whose education is usually in political science/government/public policy, who then specialize in studying a particular field or industry. It requires a deep understanding of government regulation, macroeconomics, and the specifics of the particular field in which they choose to work. So for instance, a policy analyst wouldn't need to be able to diagnose a cancer patient and prescribe treatment, but he would need to know the treatments, treatment costs, prevalence rates, and mortality rates for different types of cancers, as well as how these might vary depending on when it is detected, and the different detection methods used. He'd need to know what people were most at risk for a particular type of cancer, and when and how often they should be tested. He'd need to be able to understand what chemicals might be carcinogenic for the purposes of regulating their use. Basically, policy analysts' jobs involve talking to the doctors, the lawyers, the legislators, the administrators, the patients and their advocacy groups, and then figuring out what everyone needs to be doing. So basically, while I'm not a toxicologist, this thread is right up my alley (although I don't do much work in oncology specifically).It's good to hear you have found a place in society. That must be very important for you. I mean a good job. Hopefully well paid.

If you were to plot these on a chart, you would notice that all of these values are actually within the same confidence interval. It is incredily disturbing to see a confidence interval which is well over 50% for the first two, and almost 100% for the third. Confidence intervals are those things you always see in political polling where they say "margin of error was plus or minus 3 percent." You want as low a confidence interval as possible, because it tells you what range the value could be. So let's look at the range of values possible here:

500ug methylphenidate:
6.74-30.98

250ug methylphenidate:
2.24-12.02

Control:
0.17-7.14Ok. It's good that you have criticism. Still I believe that one should aquire all the skills that toxicologists have at the highest level for good criticism to be made. But... I'm not saying that you are bad by giving critic. For example, some law student may criticize the judge and that's good. It makes him a good law student. And even judges make mistakes. And some time that student is going to make an excellent judge, because he learned and criticized other judges.

Your criticism may proof right. Still, I read your criticism and I think I can make a few points about it. For example, you may find a population of 12 too small. I agree. But in the real world, the scientist don't have enough money to conduct the study on 100 people. So even if you do criticise them, you have to accept that 12 people is the maximum for their budget. The point is: Having criticized something does not equate to having it done better. For example... We send a rocket to mars... But the rocket does not go farther then the moon. My critic: We should equip the rocket with extra tonnes of hydrogen fuel. The problem is that we don't have extra tonnes of hydrogen fuel. So we have to go to moon, even if we could go to mars. Now with this study: We have to do with a population of 12 and depend on it even if a population of 100 was much better, until we got another study that has n=100.

Another point is. Because you lack some knowledge about toxicology your criticism may not be completely correct, only because you lack some of the knowledge. Ofcourse, basic knowledge is very good, it allowes you to understand the study more and see the weak spots. Still, while you are lacking some other toxicological skills you may produce the wrong criticism. I myself have had similar experience. If one does not know or read the entire law book, one may produce advice that is not completely good, simply because he did not got that knowledge or he didn't read the entire law book. That is why I believe that it's important to trust on authority. Well, if everybody could be a dr. it would be easy, but in reality we have to trust authority (but not always ofcourse, they make mistakes too).

Another point I like to make is that you must be subjective. Ofcourse you will criticize the studies that you don't like and you will leave the studies that you like unattended. Everybody does that, me too (it's human). So because your criticism is very subjective I find it less credible.

That is why I believe in authority. If prof. or dr. said this it must be right. But even if it wasn't right, we pretend it is right, simply because we can't do the study ourselves and we lack the skills to do the study ourselves. In university we usually listen to the professor, because we know the professor spent a great amount of his youth studying one particular kind of topic and ofcourse has great intellect. Even if the professor was wrong, we still get our grades by agreeing with the professor and that's why we are coming for. And after we got our grades we could just dump the professor somewhere.

Even if your criticism proofed right, I believe it is still rational to believe the study conclusion. Even if the judge judged completely wrong, he judged.

Preston RJ, Kollins SH, Swanson JM, Greenhill LL, Wigal T, Elliott GR, Vitiello B.
Comments on 'Cytogenetic effects in children treated with methylphenidate' by El-Zein et al.
Cancer Lett. 2005 Dec 18;230(2):292-4. Epub 2005 Jul 12. No abstract available.
PMID: 16019134 [PubMed - indexed for MEDLINE]
Well, if these scientists are much better then el-zein and/ or if these scientists have stronger evidence then we should say that they are right, I believe.

No, this I don't agree with you. El-zein was not the only author. Marvin Legator is coauthor. If you read about him, he was a legend (until his death). In fact, comparing him with wakefield is not possible and saying that their methodology is crap is completely wrong. In fact, you can't critisize their work unless you are a skilled and credible toxicologist yourself. Now... what's your real name dr...(Hyperion)???? Are you an expert in toxicology???

If you aren't then you are still allowed to critisize them, but your criticism lacks credibility. The same for me. I could one day said that professor X, expert in Y did this thing wrong. But I don't know anything about Y, so how can I accurate critisize, not even knowing what's it about.

What you can do is point to another expert that criticizes this study.
WRONG. Read my signature line. Here's what it means: The debater is irrelevant. The argument is what matters.

Anyone with the skills and knowledge of methodology can criticize quite sufficiently.

Arguing from "authority" is a sign of either a weak argument or a pseudoscientific one. It's a common fallacy that expertise matters. Here's a site that might help you through some of this:

http://www4.tpgi.com.au/users/tps-seti/baloney.html

If you truly want to know, you need to understand what evidence is and how logic can be used to deduce. You also need to understand how humans often fail to use these things correctly.

I'm not arguing. I only have an opinion that is different from yours. But I would never tell you that my opinion was the "right" one, as I am not an expert. People see things differently and don't always agree. IMO, they don't have to agree.Nobody said people have to agree.

What I'm asking is why you ignore the evidence given to you by others? Why do you continue to use the same flawed arguments (expert this, credentials that) over and over despite the obvious problems with those arguments?

BTW, I wouldn't bother criticizing any of your claims if they had no potential to mislead readers of this forum in important ways.

Ok. It's good that you have criticism. Still I believe that one should aquire all the skills that toxicologists have at the highest level for good criticism to be made.
Only if I'm criticizing the toxicology. When I criticize the methodology, what I need are empirical analysis skills.

For example, you may find a population of 12 too small. I agree. But in the real world, the scientist don't have enough money to conduct the study on 100 people. So even if you do criticise them, you have to accept that 12 people is the maximum for their budget.
In the real world, the scientist writes up a proposal for the experiment and then applies for grant money. I highly dount that he would have written up a proposal calling for hundreds of subjects, and then they gave him a grant to study 12. It just doesn't work like that.

The point is: Having criticized something does not equate to having it done better. For example... We send a rocket to mars... But the rocket does not go farther then the moon. My critic: We should equip the rocket with extra tonnes of hydrogen fuel. The problem is that we don't have extra tonnes of hydrogen fuel. So we have to go to moon, even if we could go to mars.
Ok, but to use this rather ridiculous analogy, we wouldn't fill the rocket with experiments meant for Mars, we wouldn't call it a mission to Mars, and we wouldn't have a guy sitting on the moon sending messages back pretending to be on Mars. That's basically what these studies were like, they only had the rocket fuel to get to the moon, but they're trying to pretend like they're on Mars.

Now with this study: We have to do with a population of 12 and depend on it even if a population of 100 was much better, until we got another study that has n=100.

No. I think you misunderstand. A study with n=12 is useless. You don't just make do with what you have when what you have is worthless. With a sample size that small, you simply cannot get any good data. And with regards to El-Zein's study, you're still ignoring the lack of a control group, which is what really dooms it.

Another point is. Because you lack some knowledge about toxicology your criticism may not be completely correct, only because you lack some of the knowledge. Ofcourse, basic knowledge is very good, it allowes you to understand the study more and see the weak spots. Still, while you are lacking some other toxicological skills you may produce the wrong criticism.
Ok, but there are two problems here: This only applies to my specific criticism regarding toxicology, and you don't know my level of understanding of toxicology. Also, this is a logical fallacy. You're not responding to my statements, you're simply asserting that they must be incorrect because I lack a specific credential. This is rather ironic given that both barb and I do have the expertise in empirical analysis necessary to criticize their methodology, while you do not, and yet we still explain why a particular observation is right or wrong, rather than hiding behind the fallacy of appeal to inappropriate authority or ad hominem fallacies.

Another point I like to make is that you must be subjective. Ofcourse you will criticize the studies that you don't like and you will leave the studies that you like unattended. Everybody does that, me too (it's human). So because your criticism is very subjective I find it less credible.
NO!!!!! You seem to misunderstand the ENTIRE point of scientific research and evidence-based decision making. You cannot be sujective. You have to deal with objectively observale evidence. Science isn't a particular viewpoint, it's not an ideology, it's not a set of conclusions or a set of beliefs. Science is a method.

I also fail to see where I am being subjective here. I'm not dismissing these studies because I dislike their results, I'm dismissing these studies because they are bad studies. They use small sample sizes, one of them doesn't even have controls, the other has such large confidence intervals that it almost looks like they're cherry picking data, one of them isn't even pulished, for crying out loud. The authors of these two studies simply have not made their case. They have bad methodology, questionable data sets, and they don't even attempt to explain away contrary pieces of evidence. That's why I mentioned the Wakefield comparison, these studies have very similar flaws to his, especially El-Zein's. Hell, Wakefield and El-Zein even had the exact same number of subjects.

I guess my question for you is, why is it that you find these two studies more compelling than all of the other studies, the toxicology ones on rats and the epidemiological ones on humans, which have failed to show a link, especially considering that one was basically a Wakefield clone and the other is still unpublished?

Is there a reason why you consider a sample size of 12 perfectly acceptable for one study but a sample of 529 unacceptable for the another? Which do you care more about, the accuracy of the study or the conclusions that it reached?


That is why I believe in authority. If prof. or dr. said this it must be right. But even if it wasn't right, we pretend it is right, simply because we can't do the study ourselves and we lack the skills to do the study ourselves. In university we usually listen to the professor, because we know the professor spent a great amount of his youth studying one particular kind of topic and ofcourse has great intellect. Even if the professor was wrong, we still get our grades by agreeing with the professor and that's why we are coming for. And after we got our grades we could just dump the professor somewhere.
I sent off a reply to an email yesterday to a doctor explaining to him that while I agreed with some of his suggestions, I felt that some of them were not very useful. Once you get out of college, you stop sucking up just to get grades...not that I ever did in the first place. You might get grades for doing that, but you don't get a paycheck. My boss suggested that I email our executive director as well, outlining the doc's suggestions along with my analysis for why he was wrong. The most important thing for her is whose analysis makes the most sense, not who has what degree. In scientific fields, you don't agree with someone just because of their position. Authority means nothing without evidence.


Well, if these scientists are much better then el-zein and/ or if these scientists have stronger evidence then we should say that they are right, I believe.
Doesn't matter if they're better, just if they have better evidence. My guess is that they'll just repeat much of what I've already written, they'll prolly also cite more studies which show a lack of mutagenicity and maybe more epidemiological research.

This is a very good thread, and I appreciate everyone managing to keep things civil.

My take mirrors hyperion's, namely, that the methodology was very poor. There is too much evidence that speaks against any carcinogenic effects of methylphenidate or its breakdown products, to take a small study like this and make such irresponsible assertions.

My take mirrors hyperion's, namely, that the methodology was very poor. Ok good you criticize the study. Because no study can be completely good there are always weak spots. So if you criticize them they could become better. But unless you are a skilled toxicologist yourself you know for sure if your criticism was correct. Because I might one day find myself critizing that our legal system has great gaps, but only a skilled lawyer has the knowledge to fill the gaps in our legal system.

Is there a reason why you consider a sample size of 12 perfectly acceptable for one study but a sample of 529 unacceptable for the another? Which do you care more about, the accuracy of the study or the conclusions that it reached?Because you can't make an absolute comparison in numbers between the two researches. These are different kind of researches. The one looks for chromosome breaks and the other is statistical.

It's like wow we have 100.000.000 houses in etheopia. And we have 9.000.000 houses in Amerika. So obviously etheopia has more houses.

The problem is however that etheopia houses are made from rubber and wood and the houses in amerika are made of stone.

So we ca