Sucralose, Carcinogen or Sweet Relief? Part III: DNA Breaks + Drug & Hormone Interactions | Sucralose, White Death?
Fearmongering fake, or true biohazard. This is the life-or-death- question this last installment of the sucralose trilogy will have to answer. |
Put your hazard suits on, folks!
It's obvious that I got carried away by my imagination, when I wrote this subheading, but if the same wasn't true for the author of the repeatedly cited press release, many of us are about to suffer the consequences of the potential unsafety of the hitherto unknown sucralose metabolites in our guts, pretty soon.
This is part III of a multi-part series:
I know that Mark Sisson likes to says this, but this website is not written by a machine, but by a man who has the same "short" 24h days you have... basically, what I am trying to say is that I had to split this review of the review into a "trilogy" - and be honest, you wouldn't want an article thrice as long as this one, would you?
Believe it or not, but aspartame is one out of three sweeteners Sasaki et al. tested that are not genotoxic | more about aspartame |
So what does the (almost) "real-world" evidence say?
It's unquestionably debatable whether this was a good idea or a tragic mistake, but without corresponding "real-world" assays from longer-term rodent studies, the damage that occurs in response to the DNA breaks that have been observed in in-vitro studies may well be so small that the DNA repair machinery that operates in our bodies 24/7 can fix it easily. In this case, our coroners would probably find a similar increase in non-neoplastic findings (=non-cancerous, often minimal tissue growth, where it does not belong), as they were reported by Mann et al. (see list below the red box) in a combined chronic toxicity/carcinogenicity study of sucralose in Sprague–Dawley rats and a carcinogenicity study of sucralose in mice (Mann. 2000a, 2000b). Direct evidence for the development of cancer and/or the potential epigenetic changes is yet, as Schiffman & Rother have to concede, simply not available.
Don't bake your arginine-containing anti-diabetes cookies with sucralose |
- No toxic effects even with 3% of total dietary intake in Sprague–Dawley rats; all non-neoplastic findings that occurred were of no toxicological significance and are part of the regular aging process of this strain of rats (Mann. 2000a)
- No positive results in in vivo chromosome aberration test in rats and two separate micronucleus tests in mice with doses of up to 2,000mg/kg for 5 days (Brusick. 2010)
- No effect on organ and general development, when fed to pregnant rats and rabbits in HEDs of up to 26g (rats) and 9g, respectively (Kille. 2000)
- The death of one out of 10 mice in a study by Finn and Lord that occured in response to the ingestion of the human equivalent of 1g/day of sucralse can hardly be considered conclusive evidence in favor of the "sucralose is poison hypothesis (Finn. 2000).
- The effects Mann et al. describe in a study where 3%-5% of the chow was pure sucralose is devoid of any relevance for our question (Mann. 2000a; Goldsmith. 2000). The same goes for the numerous studies where the lab animals received sucralose in amounts of >500mg/kg body weight (e.g. Finn. 2000; Kille. 2000). For a human being that would be more than 6.5g/day - and that's only if the lab animal was a rodent. For larger animals it would be even more.
Let's get on to potential endocrine effects
In view of the fact that it is pointless to speculate about the validity of the data from the positive studies in the foregoing list, I want to turn to another, the final and as we are going to see not necessarily more "productive" topic of this third and last installment of my sucralose review trilogy: The endocrine effects.
Due to sucralose not just vegans (more) may be at risk of low B12 |
To this ends we have to go back to the previously cited study by Abou-Donia et al. (2008), of which I did not tell you in the last installment of this series that it has (obviously) been under heavy attack by toxicology experts who do not necessarily doubt the validity of the study data Abou-Donia et al. present, but claim that their interpretation was irresponsible. A brief note on the criticism of the Abou-Donia study: As you'd expect it's no coincidence that the corresponding paper carries the phrase "expert panel" in it's title. It was after all written and published on request of McNeil Nutritionals, a marketer of retail products that contain the non-nutritive sweetener, sucralose, who paid the "panel of experts" to do a "independent and rigorous review of the 2008 study by Abou-Donia et al." (Brusick. 2009)
"The results in Table 1 [identical copy on the right] indicate that the magnitude of elevation for both CYP3A and CYP2D expression increased in a linear, dose-dependent manner as the dosage of sucralose increased from 3.3 to 5.5 to 11 mg/kg/d.In other words: Coincidental increases in CYP activity would not 'coincidentally' be dose-dependent, as well. If we also remind ourselves of the fact that the human equivalent doses of said 3.3, 5.5 and 11mg/kg sucralose would be (only) 43mg, 71mg and 143mg it is self-evident that we cannot simply ignore the acute and persistent increases in intestinal P-gp, CYP3A, and CYP2D (in humans this is CYP2D6; cf. Laurenzana. 1995) in the jejunum and ileum of About-Donia's hairy subjects.
This finding of significant and parallel increases in expression of two different CYP enzymes does not support the claim made by Brusick et al. (2009) that increases in CYP from sucralose ingestion were only normal biological variations."(Schiffman. 2013)
The obvious question, now, is: Does this even matter?
I mean, changes in the expression of some cryptic enzymes in the gut - who cares? After taking a look a the list of substrates that are enzymatically processed by CYP3A, alone, even the small 44% increase that occured in response to the rodent equivalent of 43mg appears relevant.
Figure 1: Important supplement drug interactions | learn more |
Unlike the increase in CYP2D6 that simply adds to the sucralose ↔ drug interactions, the corresponding increase in P-gp activity and thus the transport of chemicals from gut cells (enterocytes), back into the intestinal lumen could affect the absorption of an even wider range of both wanted and unwanted chemicals / xenobiotics with a hydrophobic and amphiphilic structure.
The net result of the increases in CYP and pGP activity is thus a significant decrease in the concentration of a xenobiotic compound on its way from the gastro-intestinal tract to the liver. Whether this amplified "first pass effect" would actually have physiologically relevant consequences in human beings is yet something we cannot tell without somebody paying for the costly research.
To complicate things, we must not ignore the possibility that "[...t]he rise in CYP expression reported by Abou-Donia et al. (2008) may result from 'autoinduction', by which sucralose enhances it own metabolism." It would thus be a second St. John’s wort, which will also increase its own metabolism by the activation of P-gp and CYP. For Hypericum perforatum extracts, which are often used as mild anti-depressants, we do already know that it affects the metabolism of an endless list of drugs and herbal supplements, and can reduce the levels of 5-alpha reduced androgens like DHT (estrogen and testosterone appear not to be influenced, though; cf. Donovan. 2005).
So what about toxicity and endocrine disruption? If we discard the potential interference with drugs and consequent "St. John's Wort"-esque side effects, I would say that the dosages that are necessary to actively induce more or less insignificant DNA damage in rodent studies, as well as the absence of any evidence of toxic effects from one of the historical single-dose or short-term sucralose studies in humans (Mezitis. 1996; Baird. 2000) make it appear very improbable that the habitual, but reasonable use of sucralose could have toxic or carcinogenic effects.
The "benefit of the doubt" is yet no acquittal, it is only my assessment of the reasoning Schiffman & Rother provide in their paper, the relevant parts of which are all based on mere hypothesis, e.g. the "IBD ↔ sucralose"-hypothesis by Qin et al. (2011, 2012), or the "there may arise different more toxic sucralose metabolites in the human vs. rat digestion tract"-hypothesis by Goldsmith (2000) and Mann (2000a) and/or rely on data from the highly disputed Abou-Donia study, the most significant result of which are (imho) still the pronounced changes in the gut microbiome (read more in the last episode of this three part series).
At the moment, it does yet still look as if you were on the "safer" side if you prefer stevia sweetened products, although I honestly have my doubts that we wouldn't observe similar effects in mice, rats and all sorts lab critters, if 5%+ of their diet was pure stevia. The dosage makes the poison, you better remember that.
References:Remember the Science Round-Up from March? The safety of stevia, is not beyond doubt either | more |
At the moment, it does yet still look as if you were on the "safer" side if you prefer stevia sweetened products, although I honestly have my doubts that we wouldn't observe similar effects in mice, rats and all sorts lab critters, if 5%+ of their diet was pure stevia. The dosage makes the poison, you better remember that.
- Abou-Donia, M. B., El-Masry, E. M., Abdel-Rahman, A. A., McLendon, R. E., & Schiffman, S. S. (2008). Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. Journal of Toxicology and Environmental Health, Part A, 71(21), 1415-1429.
- Brendler-Schwaab, S., Hartmann, A., Pfuhler, S., & Speit, G. (2005). The in vivo comet assay: use and status in genotoxicity testing. Mutagenesis, 20(4), 245-254.
- Brusick, D., Grotz, V. L., Slesinski, R., Kruger, C. L., & Hayes, A. W. (2010). The absence of genotoxicity of sucralose. Food and Chemical Toxicology, 48(11), 3067-3072.
- Brusick, D., Borzelleca, J. F., Gallo, M., Williams, G., Kille, J., Wallace Hayes, A., ... & Burks, W. (2009). Expert panel report on a study of Splenda in male rats. Regulatory Toxicology and Pharmacology, 55(1), 6-12.
- Biles, R. W., & Piper, C. E. (1983). Mutagenicity of chloropropanol in a genetic screening battery. Fundamental and Applied Toxicology, 3(1), 27-33.
- Cho, W. S., Han, B. S., Lee, H., Kim, C., Nam, K. T., Park, K., ... & Jang, D. D. (2008). Subchronic toxicity study of 3-monochloropropane-1, 2-diol administered by drinking water to B6C3F1 mice. Food and Chemical Toxicology, 46(5), 1666-1673.
- Finn, J. P., & Lord, G. H. (2000). Neurotoxicity studies on sucralose and its hydrolysis products with special reference to histopathologic and ultrastructural changes. Food and chemical toxicology, 38, 7-17.
- Goldsmith, L. A. (2000). Acute and subchronic toxicity of sucralose. Food and chemical toxicology, 38, 53-69.
- Grotz, V. L., & Munro, I. C. (2009). An overview of the safety of sucralose. Regulatory toxicology and pharmacology, 55(1), 1-5.
- Motwani, H. V., Qiu, S., Golding, B. T., Kylin, H., & Törnqvist, M. (2011). Cob (I) alamin reacts with sucralose to afford an alkylcobalamin: Relevance to in vivo cobalamin and sucralose interaction. Food and Chemical Toxicology, 49(4), 750-757.
- Kille, J. W., Tesh, J. M., McAnulty, P. A., Ross, F. W., Willoughby, C. R., Bailey, G. P., ... & Tesh, S. A. (2000). Sucralose: assessment of teratogenic potential in the rat and the rabbit. Food and chemical toxicology, 38, 43-52.
- Laurenzana, E. M., Sorrels, S. L., & Owens, S. M. (1995). Antipeptide antibodies targeted against specific regions of rat CYP2D1 and human CYP2D6. Drug metabolism and disposition, 23(2), 271-278.
- Leatherhead Food Research. (2011). The global food additives market, 5th ed., September.
Leatherhead, Surrey, UK: Leatherhead. - Mann, S. W., Yuschak, M. M., Amyes, S. J. G., Aughton, P., & Finn, J. P. (2000a). A combined chronic toxicity/carcinogenicity study of sucralose in Sprague–Dawley rats. Food and chemical toxicology, 38, 71-89.
- Mann, S. W., Yuschak, M. M., Amyes, S. J. G., Aughton, P., & Finn, J. P. (2000b). A carcinogenicity study of sucralose in the CD-1 mouse. Food and chemical toxicology, 38, 91-97.
- Rahn, A., & Yaylayan, V. A. (2010). Thermal degradation of sucralose and its potential in generating chloropropanols in the presence of glycerol. Food Chemistry, 118(1), 56-61.
- Sasaki, Y. F., Kawaguchi, S., Kamaya, A., Ohshita, M., Kabasawa, K., Iwama, K., ... & Tsuda, S. (2002). The comet assay with 8 mouse organs: results with 39 currently used food additives. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 519(1), 103-119.
- Scientific Committee on Food. (2001). Opinion of the Scientific Committee on Food
on 3-monochloro-propane-1,2-diol (3-MCPD). European Commission, Health and
Consumer Protection Directorate-General. http://ec.europa.eu/food/fs/sc/scf/out91_en.
pdf (accessed December 14, 2013) - Tritscher, A. M. (2004). Human health risk assessment of processing-related compounds in food. Toxicology letters, 149(1), 177-186.
- World Health Organization. (2002). 3-Chloro-1,2-propanediol. In Safety evaluation of certain food additives and contaminants. WHO Food Additives Series 48. http:// www.inchem.org/documents/jecfa/jecmono/ v48je18.htm (accessed December 14, 2013).