medlitГигиена и санитарияHygiene and Sanitation0016-99002412-0650Federal Scientific Center of Hygiene named after F.F. Erisman10.18821/0016-9900-2019-98-2-189-195medlit-274Research ArticleГИГИЕНА ПИТАНИЯFOOD HYGIENEК вопросу установления допустимых суточных доз химических веществ в пищевых продуктах по критериям риска здоровьюOn the issue of establishing acceptable daily intake of chemical substances in food products according to health risk criteriaШурПавел ЗалмановичShurPavel Z.

Доктор мед. наук, ученый секретарь ФБУН «Федеральный научный центр медико-профилактических технологий управления рисками здоровью населения», 614045, г. Пермь.

e-mail: shur@fcrisk.ru

MD, Ph.D., DSci., Scientific Secretary, Federal Scientific Center for Medical and Preventive Health Risk Management Technologies, Perm, 614045, Russian Federation.

e-mail: shur@fcrisk.ru

shur@fcrisk.ruhttps://orcid.org/0000-0003-2356-1145ЗайцеваН. В.ZaitsevaN. V.noemail@neicon.ruhttps://orcid.org/0000-0002-5340-9649ХотимченкоС. А.KhotimchenkoS. A.noemail@neicon.ruhttps://orcid.org/0000-0003-1240-1234ФедоренкоЕ. В.FedorenkoE. V.noemail@neicon.ruСычикС. И.SychikS. I.noemail@neicon.ruФокинВ. А.FokinV. A.noemail@neicon.ruhttps://orcid.org/0000-0002-3594-2650СуворовД. В.SuvorovD. V.noemail@neicon.ruhttps://orcid.org/0000-0002-0259-5509ЗеленкинС. Е.ZelenkinS. E.noemail@neicon.ruФБУН «Федеральный научный центр медико-профилактических технологий управления рисками здоровью населения» Федеральной службы по надзору в сфере защиты прав потребителей и благополучия человекаFederal Scientific Center for Medical and Preventive Health Risk Management TechnologiesФГБУН «Федеральный исследовательский центр питания, биотехнологии и безопасности пищи»Federal Research Center for Nutrition, Biotechnology and Food SafetyРеспубликанское унитарное предприятие «Научно-практический центр гигиены»Scientific-Practical Hygiene Center201914102020982189195Copyright © Шур П.З., Зайцева Н.В., Хотимченко С.А., Федоренко Е.В., Сычик С.И., Фокин В.А., Суворов Д.В., Зеленкин С.Е., 20202020Шур П.З., Зайцева Н.В., Хотимченко С.А., Федоренко Е.В., Сычик С.И., Фокин В.А., Суворов Д.В., Зеленкин С.Е.Shur P.Z., Zaitseva N.V., Khotimchenko S.A., Fedorenko E.V., Sychik S.I., Fokin V.A., Suvorov D.V., Zelenkin S.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rjhas.ru/jour/article/view/274

Гигиенические нормативы содержания химических веществ в пищевых продуктах в странах-членах ЕАЭС являются составной частью технических регламентов Таможенного союза и ЕАЭС. Однако к настоящему времени не для всех нормативов такого рода разработано обоснование величины их допустимых суточных доз с точки зрения допустимого риска для здоровья потребителей. Цель настоящей статьи - обсуждение основных положений установления допустимых суточных доз (ДСД) химических веществ в пищевых продуктах по критериям риска здоровью человека. Проведённый анализ проблемных вопросов установления допустимых суточных доз химических веществ в пищевых продуктах по критериям риска здоровью человека показал, что целесообразно использовать опубликованную в релевантных источниках информацию о результатах ранее проведённых исследований. При выборе отправных точек для установления ДСД или условно переносимого поступления (УПП) при наличии данных о нескольких отправных точках предпочтение стоит отдавать показателям, которые требуют применения меньшего количества модифицирующих факторов, а именно реперным уровням (BMD), установленным по результатам эпидемиологических исследований для наиболее чувствительных групп населения. Комплекс методов математического моделирования для установления гигиенических нормативов содержания химических веществ в пищевых продуктах целесообразно дополнить методом эволюционного моделирования риска здоровью, который может применяться для верификации предложенных величин. В качестве модифицирующих факторов при установлении ДСД/УПП надлежит, в первую очередь, применять факторы, учитывающие межвидовую экстраполяцию, отправные пункты для установления ДСД/УПП, экстраполяцию результатов исследований при кратковременном воздействии на сценарии постоянного воздействия. Предложенные рекомендации к обоснованию модифицирующих факторов позволят в определённой мере унифицировать их применение при расчёте ДСД химических веществ. При разработке гигиенических нормативов возможно до принятия уровней допустимого риска использовать величины приемлемого риска для здоровья: для количественной оценки - величину 1 · 10-4 пожизненного риска тяжёлого заболевания или смерти, для полуколичественной характеристики риска - коэффициент опасности 1; для анализа эволюции риска - приведённый индекс риска здоровью 0,05.

Hygienic standards for chemical admixtures contents in food products in the Eurasian Economic Union countries are an integral part of the technical regulations adopted in the Customs Union and the EEU. However, not all of them have been substantiated by the moment in relation to acceptable consumers’ health risk. The aim of this research is to discuss fundamentals for fixing acceptable daily intake (ADI) for chemical substances in food according to human health risk criteria. We analyzed problems related to fixing hygienic standards for chemical substances in food advisable in the process to apply data obtained in previous research and published in relevant literature sources. When choosing points of the establishment for fixing ADI or provisional tolerable intake (PTI) in a situation when data on several different starting points are available, one should choose such parameters that require the application of fewer modifying factors, namely reference levels (BMD) detected as for epidemiologic research results for the most sensitive population groups. It is advisable to supplement a set of mathematic modeling techniques applied for fixing hygienic standards for chemical admixtures content in food products with evolution modeling of health risk that can be applied to verify suggested values. When fixing ADI, one should primarily apply such modifying factors as those that allow for interspecies extrapolation, points of establishment for ADI/PTI, and extrapolation of research results under short-term exposure onto persistent exposure scenarios. The suggested recommendations for substantiation of modifying factors will allow unifying their application to a certain extent when calculating ADI/PTI of chemicals. Before any permissible risk levels are fixed in a process of hygienic standard development, it is advisable to apply the following permissible health risk level: for quantitative assessment, lifelong risk of a severe disease or death being equal to 1∙10-4; for semi-quantitative risk characteristics, hazard quotient equal to 1; for risk evolution analysis, reduced health risk index equal to 0.05.

гигиенические нормативыхимические веществапищевые продуктыприемлемый рискhygienic standardschemicalsfood productspermissible riskReferencesIPCS risk assessment terminology. World Health Organization. 2004. Available at: http://www.who.int/ipcs/methods/harmonization/areas/ipcsterminologyparts1and2.pdf (accessed: 31.03.2018).IPCS risk assessment terminology. World Health Organization. 2004. Available at: http://www.who.int/ipcs/methods/harmonization/areas/ipcsterminologyparts1and2.pdf (accessed: 31.03.2018).IPCS. Assessing Human Health Risks of Chemicals: Derivation of Guidance Values for Health Based Exposure Limits. Environmental Health Criteria 170. World Health Organization. Available at: http://www.inchem.org/documents/ehc/ehc/ehc170.htm (accessed: 08.09.2018).IPCS. Assessing Human Health Risks of Chemicals: Derivation of Guidance Values for Health Based Exposure Limits. Environmental Health Criteria 170. World Health Organization. Available at: http://www.inchem.org/documents/ehc/ehc/ehc170.htm (accessed: 08.09.2018).Mc Clellan R.O. Human health risk assessment: A historical overview and alternative paths forward. Inhal. Toxicol.1999; 11: 477-518.Mc Clellan R.O. Human health risk assessment: A historical overview and alternative paths forward. Inhal. Toxicol.1999; 11: 477–518.Barlow S.M., Greig J.B., Bridges J.W., Carere A., Carpy A.J., Galli C.L., Kleiner J., Knudsen I., Koлter H.B., Levy L.S., Madsen C., Mayer S., Narbonne J.F., Pfannkuch F., Prodanchuk M.G., Smith M.R., Steinberg P. Hazard identification by methods of animal-based toxicology. Food Chem. Toxicol. 2002; 40: 145-91.Barlow S.M., Greig J.B., Bridges J.W., Carere A., Carpy A.J., Galli C.L., Kleiner J., Knudsen I., Koлter H.B., Levy L.S., Madsen C., Mayer S., Narbonne J.F., Pfannkuch F., Prodanchuk M.G., Smith M.R., Steinberg P. Hazard identification by methods of animal-based toxicology. Food Chem. Toxicol. 2002; 40: 145–91.Dybing E., Doe J., Groten J., Kleiner J., O’Brien J., Renwick A.G., Schlatter J., Steinberg P., Tritscher A., Walker R., Younes M. Hazard characterization of chemicals in food and diet: Dose response mechanisms and extrapolation issues. Food Chem. Toxicol. 2002; 40: 237-82.Dybing E., Doe J., Groten J., Kleiner J., O’Brien J., Renwick A.G., Schlatter J., Steinberg P., Tritscher A., Walker R., Younes M. Hazard characterization of chemicals in food and diet: Dose response mechanisms and extrapolation issues. Food Chem. Toxicol. 2002; 40: 237–82.Crump K. A new method for determining allowable daily intakes. Fundam. Appl. Toxicol. 1984; 4: 854- 71.Crump K. A new method for determining allowable daily intakes. Fundam. Appl. Toxicol. 1984; 4: 854– 71.Mantel N., Bryan W.R. “Safety” testing of carcinogenic agents. J. Natl. Cancer Inst. 1961; 27: 455- 70.Mantel N., Bryan W.R. “Safety” testing of carcinogenic agents. J. Natl. Cancer Inst. 1961; 27: 455– 70.Barnes D.G., Daston G.P., Evans J.S., Jarabek A.M., Kavlock R.J., Kimmel C.A., Park C., Spitzer H.L. Benchmark dose workshop: Criteria for use of a benchmark dose to estimate a reference dose. Regul. Toxicol. Pharmacol. 1995; 21: 296-306.Barnes D.G., Daston G.P., Evans J.S., Jarabek A.M., Kavlock R.J., Kimmel C.A., Park C., Spitzer H.L. Benchmark dose workshop: Criteria for use of a benchmark dose to estimate a reference dose. Regul. Toxicol. Pharmacol. 1995; 21: 296–306.Report on the Benchmark Dose Peer Consultation Workshop. Washington, DC. 1996: 268.Report on the Benchmark Dose Peer Consultation Workshop. Washington, DC. 1996: 268.Dekkers S., de Heer C., Rennen M. Critical Effect Sizes in Toxicological Risk Assessment. Establishing the Breaking Point Between Adverse and Non-Adverse Changes in Toxicological Effect Parameters. TNO. Available at: http://www.tno.nl/homepage/html (accessed: 19.04.2018).Dekkers S., de Heer C., Rennen M. Critical Effect Sizes in Toxicological Risk Assessment. Establishing the Breaking Point Between Adverse and Non-Adverse Changes in Toxicological Effect Parameters. TNO. Available at: http://www.tno.nl/homepage/html (accessed: 19.04.2018).Gaylor D.W. Incidence of developmental defects at the no observed adverse effect level (NOAEL). Regul. Toxicol. Pharmacol. 1992; 15: 151-60.Gaylor D.W. Incidence of developmental defects at the no observed adverse effect level (NOAEL). Regul. Toxicol. Pharmacol. 1992; 15: 151–60.Allen B.C., Kavlock R.J., Kimmel C.A., Faustman E.M. Dose-response risk assessment for developmental toxicity: II. Comparison of generic benchmark dose estimates with NOAELs. Fundam. Appl. Toxicol. 1994; 23: 487-95.Allen B.C., Kavlock R.J., Kimmel C.A., Faustman E.M. Dose-response risk assessment for developmental toxicity: II. Comparison of generic benchmark dose estimates with NOAELs. Fundam. Appl. Toxicol. 1994; 23: 487–95.Faustman E., Allen B.C., Kavlock R., Kimmel C. Dose-response risk assessment for developmental toxocity: I. Characterization of database and determination of NOAELs. Fundam. Appl. Toxicol. 1994; 23: 478-86.Faustman E., Allen B.C., Kavlock R., Kimmel C. Dose-response risk assessment for developmental toxocity: I. Characterization of database and determination of NOAELs. Fundam. Appl. Toxicol. 1994; 23: 478–86.Kavlock R.J., Allen B.C., Faustman E.M., Kimmel C.A. Dose-response assessment for developmental toxicity. IV. Benchmark doses for fetal weight changes. Fundam. Appl. Toxicol. 1995; 26: 211- 22.Kavlock R.J., Allen B.C., Faustman E.M., Kimmel C.A. Dose-response assessment for developmental toxicity. IV. Benchmark doses for fetal weight changes. Fundam. Appl. Toxicol. 1995; 26: 211–22.Krewski D., Zhu Y., Fung K. Benchmark doses for developmental toxicants. Inhal. toxicol. 1999; 11: 579-91.Krewski D., Zhu Y., Fung K. Benchmark doses for developmental toxicants. Inhal. toxicol. 1999; 11: 579–91.Slikker W.Jr., Gaylor D. Concepts on quantitative risk assessment of neurotoxicants. Neurotoxicology Approaches and Methods. 1995: 771-6.Slikker W.Jr., Gaylor D. Concepts on quantitative risk assessment of neurotoxicants. Neurotoxicology Approaches and Methods. 1995: 771–6.Fechter L.D., Chen G.D., Rao D., Larabee J. Prediciting exposure conditions that facilitate the potentiation of noise-induced hearing loss by carbon monoxide. Toxicol. Sci. 2000; 58: 315-23.Fechter L.D., Chen G.D., Rao D., Larabee J. Prediciting exposure conditions that facilitate the potentiation of noise-induced hearing loss by carbon monoxide. Toxicol. Sci. 2000; 58: 315–23.Markowski V.P., Zareba G., Stern S., Cox C., Weis, B. Altered operant responding for motor reionforcement and determination of benchmark doses. Environ. Health Perspect. 2001: 109-621.Markowski V.P., Zareba G., Stern S., Cox C., Weis, B. Altered operant responding for motor reionforcement and determination of benchmark doses. Environ. Health Perspect. 2001: 109–621.Zhou T., Ross D.G., DeVito M.J., Crofton K.M. Effects of short-term in-vivo exposure to polybrominated diphenyl ethers of thyroid hormones and hepatic enzyme activities in weanling rats. Toxicol. Sci. 2001; 61: 76-82.Zhou T., Ross D.G., DeVito M.J., Crofton K.M. Effects of short-term invivo exposure to polybrominated diphenyl ethers of thyroid hormones and hepatic enzyme activities in weanling rats. Toxicol. Sci. 2001; 61: 76–82.Foster P., Auton T. Application of benchmark dose risk assessment methodology to developmental toxicity: An industrial view. Toxicol. Lett. 1995; 82/83: 555-9.Foster P., Auton T. Application of benchmark dose risk assessment methodology to developmental toxicity: An industrial view. Toxicol. Lett 1995; 82/83: 555–9.Budtz-Jorgensen E. Benchmark dose calculations from epidemiological data. Biometrics. 2001; 57: 698-706.Budtz-Jorgensen E. Benchmark dose calculations from epidemiological data. Biometrics. 2001; 57: 698–706.Crump K.S., van Landingham C., Shamlaye C., Cox C., Davidson P.W., Myers G.J., Clarkson T.W. Benchmark concentrations for methylmercury obtained from the Seychelles child development study. Environ. Health Perspect. 2000; 108: 257-63.Crump K.S., van Landingham C., Shamlaye C., Cox C., Davidson P.W., Myers G.J., Clarkson T.W. Benchmark concentrations for methylmercury obtained from the Seychelles child development study. Environ. Health Perspect. 2000; 108: 257–63.Rabovsky J., Fowles J., Hill M.D., Lewis D.C. A health risk benchmark for the neurological effects of styrene: Comparison with NOAEL/LOAEL approach. Risk Anal. 2001; 21: 117.Rabovsky J., Fowles J., Hill M.D., Lewis D.C. A health risk benchmark for the neurological effects of styrene: Comparison with NOAEL/LOAEL approach. Risk Anal. 2001; 21: 117.Crump K. Critical issues in benchmark calculations from continuous data. Crit. Rev. Toxicol. 2002; 32: 133-53.Crump K. Critical issues in benchmark calculations from continuous data. Crit. Rev. Toxicol. 2002; 32: 133–53.Murata K., Budtz-Jшrgensen E., Grandjean P. Benchmark dose calculations for methylmercury-associated delays on evoked potential latencies in two cohorts of children. Risk Anal. 2002; 22: 465.Murata K., Budtz-Jшrgensen E., Grandjean P. Benchmark dose calculations for methylmercury-associated delays on evoked potential latencies in two cohorts of children. Risk Anal. 2002; 22: 465.Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Available at: http://www.epa.gov/iris/index.html (accessed: 10.04.2018).Integrated Risk Information System (IRIS). U.S. Environmental Protection Agency. Available at: http://www.epa.gov/iris/index.html (accessed: 10.04.2018).Guidance Notes for Analysis and Evaluation of Repeat-Dose Toxicity Studies. OECD Series on Testing and Assessment Number 32 and OECD Series on Pesticides Number 10. Available at: https://www.oecd-ilibrary.org/environment/guidance-notes-for-analysis-and-evaluation-of-repeat-dose-toxicity-studies_9789264078482-en (accessed: 29.04.2018).Guidance Notes for Analysis and Evaluation of Repeat-Dose Toxicity Studies. OECD Series on Testing and Assessment Number 32 and OECD Series on Pesticides Number 10. Available at: https://www.oecd-ilibrary.org/environment/guidance-notes-for-analysis-and-evaluation-of-repeatdose-toxicity-studies_9789264078482-en (accessed: 29.04.2018).European Union. Revision of the Technical Guidance Document on Risk Assessment of New Notified Substances and Existing Substances. Available at: http://ecb.jrc.it/existing-chemicals (accessed: 12.04.2018).European Union. Revision of the Technical Guidance Document on Risk Assessment of New Notified Substances and Existing Substances. Available at: http://ecb.jrc.it/existing-chemicals (accessed: 12.04.2018).Report EPA/600/P-92/003C. Proposed Guidelines for Carcinogen Risk Assessment. U.S. Environmental Protection Agency. Available at: https://cfpub.epa.gov/ncea/raf/pdfs/propcra_1996.pdf (accessed: 16.04.2018).Report EPA/600/P-92/003C. Proposed Guidelines for Carcinogen Risk Assessment. U.S. Environmental Protection Agency. Available at: https://cfpub.epa.gov/ncea/raf/pdfs/propcra_1996.pdf (accessed: 16.04.2018).Anderson E., Diesler Jr. P.F., McCallum D., St. Hilaire C., Spitzer H.L., Strauss H., Wilson, J.D. and Zimmerman R. Workshop report: Key issues in Carcinogen risk assessment guidelines, society for risk analysis. Risk Anal. 1993; 13: 379-82.Anderson E., Diesler Jr. P.F., McCallum D., St. Hilaire C., Spitzer H.L., Strauss H., Wilson, J.D. and Zimmerman R. Workshop report: Key issues in Carcinogen risk assessment guidelines, society for risk analysis. Risk Anal. 1993; 13: 379–82.Онищенко Г.Г., Попова А.Ю., Тутельян В.А., Зайцева Н.В., Хотимченко С.А., Гмошинский И.В., Шевелева С.А., Ракитский В.Н., Шур П.З., Лисицын А.Б., Кирьянов Д.А. К оценке безопасности для здоровья населения рактопамина при его поступлении с пищевыми продуктами. Вестник Российской академии медицинских наук. 2013; 68 (6): 4-8.Onishchenko G.G., Popova A.Yu., Tutel’yan V.A., Zaytseva N.V., Khotimchenko S.A., Gmoshinskiy I.V., Sheveleva S.A., Rakitskiy V.N., Shur P.Z., Lisitsyn A.B., Kir’yanov D.A. About the Human Health Safety Estimation of Ractopamine Intake Together with the Food. Vestnik Rossiyskoy akademii meditsinskikh nauk. 2013; 68 (6): 4-8 (in Russian).Зайцева Н.В., Трусов П.В., Кирьянов Д.А. Концептуальная математическая модель накопления нарушений функций организма, ассоциированных с факторами среды обитания. Медицина труда и промышленная экология. 2012; 12: 40-5.Zaitseva N.V., Trusov P.V., Kir’yanov D.A. Mathematic concept model of accumulation of functional disorders associated with environmental factors. Meditsina truda i promyshlennaya ekologiya. 2012; 12: 40–5. (in Russian).Зайцева Н.В., Трусов П.В., Шур П.З., Кирьянов Д.А., Чигвинцев В.М., Цинкер М.Ю. Методические подходы к оценке риска воздействия разнородных факторов среды обитания на здоровье населения на основе эволюционных моделей. Анализ риска здоровью. 2013; 1: 15-23.Zaitseva N.V., Trusov P.V., Shur P.Z., Kiryanov D.A., Chigvintsev V.M., Tsinker M.Yu. Methodical approaches to health risk assessмеnt of heterogeneous environmental factors based on evolutionary models. Health Risk Analysis. 2013; 1:15–23.Камалтдинов М.Р., Цинкер М.Ю., Чигвинцев В.М. Подходы к идентификации параметров математической модели эволюции функциональных нарушений пищеварительной системы. Applied and Fundamental Studies. Proceedings of the 3rd International Academic Conference. St. Louis, Missouri, USA. 2013: 69-74.Kamaltdinov M.R., Tsinker M.Yu., Chigvintsev V.M. Approaches to identification of mathematical evolution model parameters for functional disorders in the digestive system [Podkhody k identifikatsii parametrov matematicheskoy modeli evolyutsii funktsional’nykh narusheniy pishchevaritel’noy sistemy]. Applied and Fundamental Studies. Proceedings of the 3rd International Academic Conference. St. Louis, Missouri, USA. 2013: 69–74 (in Russian).ISO/IEC Guide 51:1999(E) Second Edition. International Organization for Standardization: Geneva, Switzerland, 1999ISO/IEC Guide 51:1999(E) Second Edition. International Organization for Standardization: Geneva, Switzerland, 1999.Оценка рисков для организма человека, создаваемых химическими веществами: обоснование ориентировочных величин для установления предельно допустимых уровней экспозиции по показателям влияния на состояние здоровья. Всемирная Организация здравоохранения. Москва: Изд-во Медицина. 1995: 85Assessment of risks for a human body caused by chemicals: substantiation of rough values for fixing maximum permissible exposure levels as per influence on health [Otsenka riskov dlya organizma cheloveka, sozdavaemykh khimicheskimi veshchestvami: obosnovanie orientirovochnykh velichin dlya ustanovleniya predel’no dopustimykh urovney ekspozitsii po pokazatelyam vliyaniya na sostoyanie zdorov’ya]. Vsemirnaya Organizatsiya zdravookhraneniya. Moscow: Izd-vo Meditsina. 1995: 85. (in Russian).

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