CDC eyes chemicals' level in humans

Dioxins in Shampoos, Skin Creams

Why Perfumes and Fragrances can be Harmful.

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Personal Care and Cosmetic Products May be Carcinogenic

18 Cosmetic Myths

Are Parabens Safe?

Personal Care and Cosmetic Products May be Carcinogenic

What is Propylene Glycol?

Paraben Preservative Safety – Estrogenic or Not

"Certain ingredients are only chemically stable in products if the pH (acid/base) is adjusted to the ideal pH. This is especially true of paraben preservatives used in personal care products.  In addition, the parabens work as preservatives better in certain pH ranges.  Often the amount of acid or base needed to adjust the pH is only drops per 100 gallons of product.  The MSDS of these caustic substances are not reflective of just how safe they are after being diluted in hundreds of gallons of product. Literally, they are safer than water in these applications because they adjust the pH of the product to a neutral pH for the skin, thus decreasing the likelihood of skin irritation.  There simply is no basis for criticizing the use of pH adjusters."

Background:  Alkyl-hydroxy benzoate preservatives (Parabens) are chemically very similar to alkyphenol, a known estrogenic substance in many species of animals.  Since parabens are extensively used in a wide range of products, many have wondered if the epidemiological studies showing a decline in human male reproductive health¹might be linked to additive doses of mild estrogens (xenoestrogens) in the environment.² The ubiqultous terminology of known estrogens and xenoestrogens was introduced into general public health information in 1997 by Routledge and Sumpter.³By their own admission, little is known about the potential risks to humans following exposure to “currently labeled” xenoestrogens, or their potential routes and levels of exposure⁴

Data available concerning paraben estrogenicity:  JP Sumpter appears to be the catalyst behind the current scare tactics being generated worldwide.  Professor Sumpter is a well-known educator and author of primary literature concerning fish exposed to environmental contaminants.  He has been the co-author of 66 scientific papers.  Dr. Sumpter has been the primary author of 17 papers, 14 being actual research on fish in the aquatic environment.  The other 3 papers were editorials with an exaggerated environmental point of view (“Male sexual development in “a sea of oestrogen⁵ The majority of his literature deals with fish and estrogens in the aquatic environment.  However, these studies cannot be extrapolated to humans.  In his most thorough and knowledgeable paper related to humans, the authors try and relate rat and mice studies to humans ⁴  The recombinant yeast estrogen screen developed by Routledge and Sumpter in 1996 ⁶ is limited because it cannot assess barriers such as skin and mucous or metabolic enzymes that break down parabens within the skin, blood, digestive tract, or liver.  This is pointed out in the 1998 paper (4) when these parabens were given orally or subcutaneously to immature rats at monstrous doses (800mg MP/kg/day).  The uterus weights of these rats did not increase.  Furthermore, in even large doses (1200mg MP/kg/day)given subcutaneously, where uterus weight did increase, neither methylparaben or butylparaben caused premature vaginal opening in any experiment (a common result of giving estradiol).  Apparently no true estrogenic and target effect could be induced by parabens at even ridiculously large doses.

It must be assumed from the 1998 Routledge and Sumpter paper that the primary author (Dr. Routledge) is not at all convinced that parabens cause estrogenic effects.  The paper outlines in great detail the penetration of parabens through the statum corneum (the outermost barrier layer of the skin).  It then details how esterase enzymes between the statum corneum and the dermal layers quickly metabolize much of the parabens.  It has been known for years that any paraben that is absorbed is rapidly metabolized and excreted⁷ Any remaining paraben is rapidly hydrolyzed in the blood.) Various researchers, however, have found trace amounts of unmetabolized paraben in the urine. ⁴,⁷)  Routledge is cautious to point out that there is a very small chance that some of this trace amount may reach the estrogen receptor and cause an effect.  The effect has never been noted, but he wants to call our attention to the need for a more specific test to incorporate all of these variables (absorption, metabolism, receptor site effect, etc.)

The final sentence in the 1998 Routledge and Sumpter paper calls for a more detailed evaluation of the response of the rodent endocrine system to these chemicals.  Since Sumpter in his 83 clinical studies never tries to relate fish hormonal systems to humans, it can be assumed that correlations have not been proven.  This variation of effects, even in rodents, is starkly evident.  Fisher JS, et al. Demonstrated that parabens are not estrogenic in rats⁹However, Hossaini A, et al, demonstrated a weak estrogenic effect in rats given huge subcutaneous doses, but no effects evident in mine.¹⁰The only common paraben pharmacokinetic link between mice, rats and humans appears to be that none of the 3 species absorb parabens from the gut.  It appears that the rodent model in treating for paraben estrogenicity should be abandoned although.  There is no doubt that researchers should continue to evaluate xenoestrogens, especially if these so-called xenoestrogens have any kind of estrogenic effect in humans.  New tests were results can be extrapolated to humans would be desirable.

Recommendation:  Paraben’s are still the success story of preservatives.  Several governmental agencies profess them to be practically nontoxic. ¹¹ ¹³The best synopsis of paraben safety is found in the 1998 Routledge and Sumpter paper that Dr. Sumpter is using as ammunition against parabens.  The popular use of paraben preservatives in cosmetics and toiletries arises from their:  1) low toxicity  2) inertness 3) broad spectrum of activity (against microbes) 4) worldwide legislative acceptance 5) biodegradability 6) relatively low cost 7)almost universally considered to be safer than the alternatives ⁸chemical stability in relation to pH (most effective at body pH) 9) temperature stable.

We hope to eventually find natural preservatives that can match the parabens safety and effectiveness.  If and when that happens, most worldwide governmental agencies will probably ban the use of these new preservatives from their countries because “they are not as well studies as parabens”.  This is a paradox of safety; how can a new preservative show an impressive track record against 30 years of paraben use?

1. Carlsen E, et al. Environ Health Perspect 1995;103(Suppl 7):137-39.  Declining semen quality and increasing incidence of testicular cancer: is there a common cause?

2. Shapre RM, et al. Environ Health Perspect 1995;103:1136-43.  Gestational and lactational exposure of rats to xenoestrogens results in reduced testicular size and sperm production.

3. Routledge EJ and Stumpter JP. J Biol Cehm 1997;272:3280-88. Structural feataures of alkylphenolic chemicals associated with estrogenic activity.

4. Routledge EJ, et al. Toxicol Applied Pharmacol 1998;153:12-19.  Some Alkyl hydroxy benzoate preservatives (parabens) are estrogenic

5. Sumpter JP and Jobling S. Lancet 1993;342:124-25. Male sexual development in “a sea of oestrogen”.

6. Routledge EJ and Sumpter JP. Environ Toxicol Chem 1996:272:3280-88 Estrogenic activity of surfactants and some of their degradations roducts assessed using a recombinant yeast screen.

7. Elder RL J Am Coll Toxicol 1984;3:147-209.  Final report on the safety assessment of methylparaben, ethylparaben, propylparaben, and butylparaben.

8. Kiwada H, et al J Pharm Dyn 1980:3:353-63.  The study on the biological fate of paraben at the dose of practical usage in rat. II.  The pharmacckinetic study on the blood concentration after the administration of ethyl paraben or p-hydroxybenzoic acid.

9. Fisher JS, et al.  Environ Health respect 1999;107:397-405.  Effect of neonatal exposure to estrogenic compounds on development of the excurrent ducts of the rat testis through puberty to adulthood.

10. Hossaini A, et al.  Fod Chem Toxicol 2000 Apr,38(4):319-23.  Lack of oestrogenic effects of food preservative (Parabens) in uterotrophic assays.

11. BIBRA working group. TA: Toxicity profle. The British Industrial Biological Research Association 1989 Vt:10.

12. Willis L J Amer Coll of Toxicology 1995;14:364-72.  Final report on the safety assessment of isobutylparaben and isopropylparaben.

Paraben Preservative Safety Revisited

None of us like the general idea of using preservatives.  It is a basic premise of Neways International not to use preservatives unless absolutely necessary.  However, many great Neways products must be protected against microbial contamination.  When it is necessary, we most often turn to preservatives that have been shown to be safer than other preservatives.  These are methyl-parabens and propyl-parabens.  Be assured that the scientists at Neways are constantly scanning the media and studies to determine if new effective, but more important, safer ingredients are available.  At least once a year, preservatives come under the scrutiny of various consumer advocacy groups.  This is in the best interest of everyone.

Consumer advocacy groups often refer to the same old studies, one fifteen years old and the other twenty-five years old, to substantiate their claims of parabens toxicity.  The 1975 study (by Moriyama, I) ¹ shows a possible teratogenic effect on pregnant rats by ethyl-p-hydroxy-benzoate. There have been no further studies to substantiate this possible effect.  In fact the huge doses they used introduces bias that can not be accounted for in their conclusions.  The 1985 study states that butyl p-hydroxybenzoate, and isobutyl p-hydroxybenzoate may have caused some “tumorogenicity” with huge does in mice that already had pre-existing cancer cells.²  They did not mention the word carcinogenicity.  It appears that this study is not applicable to our use of parabens because it uses such high doses of this butyl-type parabens preservative.  The reason these butyl, ethyl, and isopropyl parabens are not in general use is because of continuing watchdog studies (such as Nakagawa’s 1998 study showing mitochondrial toxicity of parabens in rat hepatocytes^3.  This type of study demonstrates the toxicities of certain parabens down to their cellular mechanism.  Neways has consciously chosen not to use these parabens because there are safer options; namely methyl or propyl parabens.

Most recently, some animal studies showed that parabens may have a weak estrogenic (100,000 times less potent uterotrophic effect in-vivo than estradio) effect₄ which could be interpreted indirectly as carcinogenic.  Since then studies have tried to duplicate this effect and found that uterine weights of mice and rats did increase slightly, but determined this was not an effect of estrogenic activity₅ as hypothesized in the earlier study.  We are no longer concerned with this issue

There are some very recent studies of interest. They involved using a preservative containing anesthetic agent in the spinal fluid and brain _6,7   The authors used the parabens-preserved medicine directly in the cerebrospinal fluid and found no evidence of neurologic toxicity due to the parabens.  Neways interprets that if no toxicity is seen when the parabens are applied in such a direct manner to body fluids, it is unlikely parabens-containing products that are used topically or ingested would induce toxicity.  In fact, the researchers have petitioned the FDA to use this parabens-containing drug, and are now conducting phase I and II clinical trials

A chemical cousin of the parabens, benzoic acid, is used even more widely than the parabens as a preservative.  Parabens are often reserved for cases where benzoic acid is sensitizing to the epithelium. Most eye drops now contain parabens because they so rarely cause contact dermatitis.  A report (by Tosti, A)₈ stated that with as many people currently using products containing parabens, contact dermatitis cases are insignificant.

There was one study from 1979 possibly linking methyl-p-hydroxybenzoate to a test using the 59 section of rat genome₉.  This test was not to indicate mutagencity, but simply to develop a possible assay for future use.  Eleven years later this test was declared by one of the original authors, as giving mixed results when compared with other chromosomal tests₁₀.

Discussion:  Paraben’s are the success story of preservatives. No one sums it up better than the British Industrial Biological Research Association (BIBRA) working group: “Repeated oral administration (of parabens) was without reproductive toxic potential in a range of species…(parabens) by injection gave no indication of chemical carcinogenic potential¹¹  In 1995 Willis, L in the Journal of the American College of Toxicology stated that parabens in normal concentrations (0.8%) were “practically nontoxic, non-mutagenic, and non-carcinogenic in sub-chronic and chronic toxicity studies¹².  Because of this study the Cosmetic Ingredient Review Expert Panel concluded that parabens can be safely used as cosmetic ingredients.

1. Moriyama I, et al. Acta Obstet Gynaecol Jpn 1975;22(2):94-106.  Teratogenic effects of food addictive ethyl-p-hydroxy-benzoate studied in pregnant rats

2. Inai K, et al, Food Chem Toxicol 1985;23(6);575-78. Tumorigenicity study of butyl and isobutyl-p-hydroxy-benzoates administered orally to mice

3. Nakagawa Y, et al. Biochem Pharmacol 1998;55(11):1907-14.  Mechanism of –hydroxybenzoate ester-induced mitochondrial dysfunction and cytotoxicity in isolated rate heptocytes

4. Routledge EJ, Sumpter JP, et al.  Toxicol Appl Pharmacol 1998 Nov;153(1):12-19.  Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic

5. Hossaini A, et al.  Food Chem Toxicol 2000 Apr;38(4):319-23.  Lack of oestrogenic effects of food preservatives (parabens) in uterotrophic assays.

6. Gurum MS et al. Anesth Analg 1997 Aug;85(2):317-23. Studieson the safety of glucose and parabens containing neostigmine for intrathecal administration.

7. Eisenach JC et al, Anesth Analg 1997 Oct;85(4);842-6.Phase I human safety assessment of intrathecal neostigmine containing methyl- and propyl- parabens

8. Tosti A, et al.  Contact Dermatitis 1989 Jul;21(1):49-51. Dermal contact dermatitis from benzylparaben

9. Matsuoka A, et al.  Mutation Research 1979;66:277-90.  Chromosomal aberration tests on 29 chemical combined with 89 mix in-vitro

10. Sofuni T, et al.  Mutat Res 1990 Jun;241(2):175-213.  A comparison of chromosome aberration induction by 25 compounds tested by two Chinese hamster cell (CHL and CHO) systems in culture.

11. BIBRA working group.   TA:Toxicity profile. The Britchi Industrial Biological Research Association 1989 VI:10.

12. Willis L, et al. J Am Coll Toxicol 1995;14(5):364-72.  Final report on the safety assessment of isobutylparaben and isopropylparaben

    

Parabens (Methyl and Proply hydroxybenzoates) 

BACKGROUND:  Methyl and Propyl Parabens are widely used as preservatives in personal care and cosmetic products.  Like many preservatives their safety has been questioned and tested in numerous laboratory tests.  Moriyama, I et al in 1975 implicated the preservative ethyl-p-hydroxy-benzoate to be teratogenic in pregnant rates.¹ Their conclusions could not be substantiated by their data, however, and subsequent studies have not substantiated this theory.²  The same holds true with studies implicating methyl and propyl parabens as carcinogens.  Recently a study tried to show estrogenic activity from parabens,³ but was refuted by a more credible study.⁴  Mutagenicity studies have also exonerated parabens, ^5.6 although the use of parabens will always remain controversial.  Because parabens can kill microbial cells, in very high doses they can also damage certain human cells, as all currently available preservatives do.  This mechanism has been elucidated recently, and seems to be a reasonable risk to mitochondrial components of hepatocytes. ⁸  However, the levels used in Neways products are very low, and would show none of the markers of liver toxicity.  Overall, Parabens are the least irritating preservatives known.⁸ They are used in “sensitive-eye” products, products injected directly into the cerebrospinal fluid, and in certain ‘hypo-allergenic” cosmetics. ⁹  Even the most out-spoken critic of parabens (JP Sumpter) published the following synopsis concerning the wide-spread use of parabens; parabens boast: 1) low toxicity 2) inertness 3) broad spectrum of activity [against microbes]  4)worldwide legislative acceptance  5) biodegradability  6) relatively low cost  7) almost universally considered to be safer than the alternatives  8) chemical stability in relation to pH [most effective at body pH] 9) temperature stable. ¹⁰  Parabens are present in Neways Endau, Imperfection Lotion, Replenishing Mist, Retention Plus, Snap Back, Wrinkle Drops, Indulge Bubble Bath, 2^nd Chance Conditioner, NightScience Moisturizer, Skin Enhancer Moisturizer, Tender Care Lotion, Milky Cleanser, TLC Cleanser, Sculpting Gel, Super Booster, Great Tan, Rebound, and Tanacity.

Safety Concerns:  Although parabens occasionally cause contact dermatitis, a report by Tosti, A stated that considering the vast number of people currently using products containing parabens, contact dermatitis cases are insignificant ⁸

Safety Profile:  These two parabens used together in low concentrations score a very solid 8 out of 10.  This is impressive considering parabens are so toxic to bacteria.

Parabens at the Human Estrogen Receptor

Background:  It is apparent that some high molecular weight Parabens bind at rodent estrogen receptors, and affect estrogen targets.⁽¹⁾  It also is known that other Parabens may interact with the human estrogen receptor but do not illicit any perceptible may interact with the human estrogen receptor but do not illicit any perceptible estrogenic effects. ¹ Furthermore, the association of phytoestrogens at the receptor may have protective anti-estrogenic effects. ⁽²⁾ The yeast/human estrogen receptor test (YES test) cannot differentiate between estrogenic and anti-estrogenic action at the receptor, thus the test can give false positive results.  Epidemiologic evidence of Asian women show they have a much lower incidence of breast cancer and are heavy users of soy based products containing phytoestrogens. ⁽³⁾ Recent findings using the YES test should guide us to use caution when selecting paraben preservatives, however, it must be remembered that Parabens are the current “gold-standard” among preservatives in the food and cosmetics industries.

New Studies on the Human Estrogen Receptor:  Okubo published data showing that Parabens may have estrogen  receptor (ER) dependent estrogenic activities, but that these effects may or may not be signaled to cells in the same way 17-beta-estradiol signals cells. ⁽⁴⁾ Competitive binding to human ER alpha and Ebbets revealed that the Parabens with longer side-chains (higher molecular weight) showed greater affinity for estrogen receptors.  This data corroborates earlier studies showing that small Parabens like methyl-, ethyl-, and propyl- Parabens probably have no estrogenic effects because of poor affinity for the estrogen receptor.⁽⁵⁾  In addition, it is highly unlikely any of these Parabens would ever reach the receptor because of rapid enzymatic metabolism of Parabens in tissues and blood.⁽⁶⁾

Another new study was performed specifically to investigate whether estrogenic activity of Parabens can be detected in estrogen-sensitive human cells.⁽⁷⁾ They could not document any activity.  Fortunately, they promised future work would address the extent to which Parabens can accumulate in these sensitive tissues.  When injecting massive doses directly inside the body, certain Parabens Illicit estrogen effects in animal models. ⁽⁵⁾ Topically applied Parabens are not likely to ever accumulate in sensitive tissues because they are rapidly metabolized in the dermal layers.  If a few molecules did pass into the blood stream these would assuredly be metabolized before any accumulation could occur in sensitive tissues. ⁽⁸⁾ These scientists corroborated earlier evidence showing that stereo-Isomeric crystalline structure of the Parabens matches the human estrogen receptor.  This tells us that further studies are needed to determine if week affinity for the receptor will correspond to any estrogenic effect in the body, although this looks unlikely at the present time.

Recommendation:  It is premature to link short side-chain Parabens to human estrogenic activity.  In fact, this association could prevent scientists from demonstrating that some of these molecules may indeed be protective anti-estrogens, or have estrogen balancing effects as seen with cancer reduction associated with soy.⁽⁹⁾

1. Fisher JS, et al.  Environ Health respect 1999;107:397-405.  Effect of neonatal exposure to estrogenic compounds on development of the excurrent ducts of the rat testis through puberty to adulthood.

2. Parisaul HB, et al. Brain Res Mol Brain Res 1999 Apr 6;67(1):165-71.  Regulation of estrogen receptor beta mRNA in the brain: opposite effects of 1 7beta-estradiol and the phytoestrogen, coumestrol.

3. Cotroneo MS, et al.  Carcinogenesis 2002 Sep;23(9):1467-74. Gemistein action in the prepubertal mammary gland in a chemoprevention model.

4. Okubo T, et al.  Food Chem Toxicol 2001 Dec;39(12):1225-32. ER-dependent estrogenic activity of Parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ERalpha and PR.

5. Hossaini A, et al.  Fod Chem Toxicol 2000 Apr,38(4):319-23.  Lack of oestrogenic effects of food preservative (Parabens) in uterotrophic assays.

6. Kiwada H, et al J Pharm Dyn 1980:3:353-63.  The study on the biological fate of paraben at the dose of practical usage in rat. II.  The pharmacckinetic study on the blood concentration after the administration of ethyl paraben or p-hydroxybenzoic acid.

7. Byford JR, et al.  J Steroid Biochem Mol Biol 2002 Jan; 80(1):49-60. Oestrogenic activity of Parabens in MCF7 human breast cancer cells.

8. Routledge EJ, et al. Toxicol Applied Pharmacol 1998;153:12-19. Some alkyl hydroxy benzoate preservatives (Parabens) are estrogenic

9. Rowlands JC, et al.  Food Chem Toxicol 2002 Dec;40(12):1767-74, Estrogenic and antiproliferative properties of soy sapogenols in human breast cancer cells in vitro.