Background

farmaec

FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology

ФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология

2070-49092070-4933

IRBIS LLC

10.17749/2070-4909/farmakoekonomika.2024.263

farmaec-1030

Research Article

REVIEW ARTICLES

ОБЗОРНЫЕ ПУБЛИКАЦИИ

Problems of using phenol (hydroxybenzene) and parabens as pharmaceutical stabilizers: analysis using machine learning methods

Проблемы использования фенола (гидроксибензола) и парабенов в качестве стабилизаторов фармацевтических средств: анализ с применением методов машинного обучения

https://orcid.org/0000-0002-2659-7998

Торшин

И. Ю.

Torshin

I. Yu.

Торшин Иван Юрьевич – к.ф-м.н., к.х.н.

WoS ResearcherID: C-7683-2018

Scopus Author ID: 7003300274

ул. Вавилова, д. 44, корп. 2, Москва 119334

Ivan Yu. Torshin – PhD (Phys. Math.), PhD (Chem.)

WoS ResearcherID: C-7683-2018

Scopus Author ID: 7003300274

44 corp. 2 Vavilov Str., Moscow 119334

https://orcid.org/0000-0002-7663-710X

Громова

О. А.

Gromova

O. A.

Громова Ольга Алексеевна – д.м.н., профессор

WoS ResearcherID: J-4946-2017

Scopus Author ID: 7003589812

ул. Вавилова, д. 44, корп. 2, Москва 119334

Olga A. Gromova, Dr. Sci. Med., Prof.

WoS ResearcherID: J-4946-2017

Scopus Author ID: 7003589812

44 corp. 2 Vavilov Str., Moscow 119334

unesco.gromova@gmail.com

Федеральный исследовательский центр «Информатика и управление» Российской академии наукРоссияFederal Research Center “Computer Science and Control”, Russian Academy of SciencesRussian Federation

2025

02052025

181125139

2025

Торшин И.Ю., Громова О.А.

Torshin I.Y., Gromova O.A.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.pharmacoeconomics.ru/jour/article/view/1030

Background

Background. Phenol and parabens exert bactericidal properties, are relatively low-toxic (in acute toxicity tests) and are used in pharmaceutical, cosmetic and food industries as stabilizers/preservatives for the final product. Despite their widespread use, the long-term toxicological effects of phenol and parabens remain largely unexplored.

Objective

Objective: To conduct an analysis of the results of basic and clinical studies on chronic toxicity of phenol and parabens.

Material and methods

Material and methods. The study included 544 articles found using the query “Preservatives, Pharmaceutical [MeSH Terms] AND Phenol [MeSH Terms]” in the PubMed/MEDLINE biomedical publications database. Methods of topological and metric analysis of big data were applied, developed in the scientific school of Academician of the Russian Academy of Sciences Yu.I. Zhuravlev. Keywords were sorted by empirical Rudakov–Torshin informativeness functionals in the context of combinatorial theory of solvability, followed by combinatorial testing of solvability to find terms with the greatest informativeness.

Results

Results. Despite the existence of individual studies on the acute toxicity of phenol and its derivatives (including parabens), the chronic toxicity of phenol and parabens remains poorly understood. This fact is indicated not only by a lack of carefully performed research, but also by the information in safety data sheets supplied by manufacturers of the relevant substances. The associations of phenol and paraben blood levels with certain chronic pathologies in humans have been insufficiently studied. At the same time, the authors of fundamental research, if not “sound the alarm,” then strongly underline the need to conduct large-scale clinical trials on the long-term toxic effects of phenol and parabens. Firstly, this is due to complex estrogen-like effect of phenol and parabens, including (1) effects on estrogen sulfotransferases, (2) direct interactions with estrogen receptors, (3) influence on the expression of steroid receptor genes. Secondly, the available data from fundamental research indicate that phenol/parabens obviously stimulate the the molecular mechanisms of oncogenesis pathophysiology (systematic disturbances in gene expression and corresponding changes in the structure of organ tissues). Thirdly, teratogenic and other toxic effects on the embryo and pregnancy were demonstrated not only in experimental studies (neurotoxicity and teratogenesis in animal models), but also in clinical observations (metabolic disorders in a pregnant woman, including the metabolism of purines and fatty acids beta-oxidation, hyperactivity and/or excess body weight in children, asthma, thyroid dysfunction, etc.).

Conclusion

Conclusion. Findings from basic research and selected clinical studies dictate an urgent need to examine the association of phenol/paraben blood levels with chronic pathologies in large-scale clinical trials with cross-sectional and longitudinal design. The lack of indication on toxic effects of parabens and phenols in certain clinical studies may just be an artifact of incorrect data analysis.

Актуальность

Актуальность. Фенол и парабены проявляют бактерицидные свойства, сравнительно малотоксичны (в тестах на острую токсичность) и используются в фармацевтической, косметической и пищевой промышленности как стабилизаторы/консерванты конечного продукта. Несмотря на повсеместное применение, долговременные токсикологические эффекты фенола и парабенов остаются практически не исследованными.

Цель

Цель: провести анализ результатов фундаментальных и клинических исследований по хронической токсичности фенола и парабенов. Материал и методы. В анализ включены 544 статьи, найденные по запросу “Preservatives, Pharmaceutical [MeSH Terms] AND Phenol [MeSH Terms]” в базе данных биомедицинских публикаций PubMed/MEDLINE. Использованы методы топологического и метрического анализа больших данных, разрабатываемые в научной школе академика РАН Ю.И. Журавлёва. Ключевые слова сортировались по эмпирическим функционалам информативности Рудакова–Торшина в контексте комбинаторной теории разрешимости с последующим комбинаторным тестированием разрешимости для нахождения терминов с наибольшей информативностью.

Результаты

Результаты. Несмотря на существование отдельных исследований острой токсичности фенола и его производных (в т.ч. парабенов), хроническая токсичность фенола и парабенов остается малоизученной. На этот факт указывает не только отсутствие тщательно выполненных исследований, но и информация в паспортах безопасности, предоставляемая самими производителями соответствующих веществ. Слабо исследованы ассоциации уровней фенола и парабенов в крови с теми или иными хроническими патологиями у человека. В то же время авторы фундаментальных работ если не «бьют тревогу», то настоятельно подчеркивают необходимость проведения крупномасштабных клинических исследований долговременного токсического действия фенола и парабенов. Во-первых, это связано с комплексным эстрогеноподобным действием фенола и парабенов, включающим: 1) воздействие на эстроген-сульфотрансферазы; 2) непосредственные взаимодействия с эстрогеновыми рецепторами; 3) влияние на экспрессию генов стероидных рецепторов. Во-вторых, имеющиеся данные фундаментальных исследований указывают на очевидное стимулирование фенолом/парабенами молекулярных механизмов патофизиологии онкогенеза (систематические нарушения экспрессии генов и соответствующие изменения структуры тканей органов). В-третьих, продемонстрировано тератогенное и прочее токсическое воздействие на эмбрион и беременность, причем не только в экспериментальных исследованиях (нейротоксичность и тератогенез на моделях животных), но и в клинических наблюдениях (нарушения метаболизма организма беременной, в т.ч. метаболизма пуринов и бета-окисления жирных кислот, гиперактивность и/или избыточная масса тела у детей, астма, дисфункция щитовидной железы и др.).

Заключение

Заключение. Результаты фундаментальных и отдельных клинических испытаний диктуют насущную необходимость изучения ассоциации уровней фенола/парабенов в крови с хроническими патологиями в рамках крупномасштабных клинических исследований поперечного и продольного дизайна. Отсутствие указания на токсическое действие парабенов и фенолов в тех или иных публикациях может быть всего лишь артефактом неверно проведенного анализа данных.

фенолпарабенытоксичностьфармацевтические консервантыхондропротекторынейропротекторы

Phenolparabenstoxicitypharmaceutical preservativeschondroprotectorsneuroprotectors

Работа выполнялась по государственному заданию № 0063-2019-0003 «Математические методы анализа данных и прогнозирования» с использованием инфраструктуры Центра коллективного пользования «Высокопроизводительные вычисления и большие данные» (ЦКП «Информатика») ФИЦ «Информатика и управление» РАН (г. Москва)

The research was conducted under the government contract No. 0063-2019-0003 “Mathematical methods of data analysis and forecasting” using the infrastructure of the Shared Research Facilities “High Performance Computing and Big Data” (SRF “Informatics”), of FRC “Computer Science and Control”, RAS (Moscow)

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The authors declare that there are no conflicts of interest present.