Based on the own experimental data and comprehensive analysis of national toxicometric indicators and MPC of 330 chemicals in different media (working area, atmospheric air and water reservoirs), as well as 265 standards used in the US and the EU, a systematic approach was designed and implemented with the purpose of substantiating the chemicals hygienic standards in different media. It takes into consideration the parameters of toxicity and cumulative properties of standardized substances which are manifested integrally by the reliability standard value, determined by the ratio of LC50 (LD50)/MPC wz , which correlates with the corresponding relations of foreign standards. At the same time, MPC wz plays an important part in the parameters of the system creation. Implementation of the methodological guide developed by the authors and approved by the Ministry of Public Health of Ukraine provided the opportunity to significantly reduce uncertainties in the process of hygienic standardization, improving the reliability of newly developed standards and correction of existing standards on the basis of newly accumulated experimental and clinical data. Further development of systematic approach to the hygienic standards will more successfully solve challenges of hygiene and quantitative toxicology, as the assessment of acceptable risk, the combined effects of chemical substances, the substantiation of regional, emergency standards, integrated regulatory support of chemical safety of the workers and the population as whole.