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      The reference values in the interpretation of toxicological data

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          Abstract

          The worldwide gradual expansion of industrialization has led to a dramatic increase in the production and use of chemical substances. This has resulted in a greater dispersion of these elements in the environment and in an increased exposure of the general population and workers. In this scenario, a thorough knowledge of exposure levels is needed in order to assess chemical risks in environmental and occupational settings. Biological monitoring is among the most useful tools for assessing exposure. However, in order to provide really effective guidance in the application/implementation of risk management measures, biomonitoring results need to be compared with appropriate references. Reference values (RVs) are an excellent resource since useful information for a correct interpretation of toxicological data can be obtained by comparing them with biomonitoring results. In the field of public health, this may enable us to identify potential sources of exposure, define the principal and most frequently exploited routes of exposure, and outline chemical absorption. Similarly, in occupational medicine, RVs can be used to give meaning to biomonitoring findings, especially when a biological limit value is not available for the chemical in question. Furthermore, these values are a valid tool for assessing exposure to chemical carcinogens. Therefore, by integrating reference values in an appropriate and complete system of guide values that also includes action levels and biological limit values, we could obtain both an adequate assessment of exposure and a better understanding of toxicological data.

          Translated abstract

          « I valori di riferimento nell’interpretazione dei dati tossicologici ». La progressiva industrializzazione a livello mondiale ha comportato un aumento della produzione e dell’uso di sostanze chimiche, causandone una crescente dispersione nell’ambiente e un incremento dell’esposizione umana. Una conoscenza adeguata dei livelli di esposizione a tali sostanze appare essenziale per la valutazione del rischio chimico. A tal fine, uno degli strumenti più importanti per la valutazione dell’esposizione è il monitoraggio biologico. Tuttavia, i risultati del biomonitoraggio, per essere utili nel suggerire l’adozione/implementazione di misure di gestione del rischio, devono essere confrontati con riferimenti appropriati. In un contesto di sanità pubblica, il confronto tra i risultati del biomonitoraggio e i valori di riferimento, fornisce informazioni utili per interpretare correttamente i dati tossicologici permettendo di identificare potenziali fonti e principali vie di esposizione e definire l’assorbimento delle sostanze chimiche. Analogamente, per quanto riguarda la medicina del lavoro, questi valori possono essere utilizzati per interpretare i risultati del biomonitoraggio, specialmente laddove non sia disponibile un valore limite biologico per la sostanza chimica di interesse. Inoltre, il loro impiego è valido anche per la valutazione dell’esposizione ad agenti cancerogeni. Pertanto, l’integrazione dei valori di riferimento in un sistema di valori guida appropriato e completo, inclusivo di livelli di azione e valori limite biologici, garantisce di ottenere sia una valutazione adeguata dell’esposizione che una maggiore e più approfondita comprensione dei dati tossicologici.

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          Most cited references57

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          Human biomonitoring: state of the art.

          Human biomonitoring (HBM) of dose and biochemical effect nowadays has tremendous utility providing an efficient and cost effective means of measuring human exposure to chemical substances. HBM considers all routes of uptake and all sources which are relevant making it an ideal instrument for risk assessment and risk management. HBM can identify new chemical exposures, trends and changes in exposure, establish distribution of exposure among the general population, identify vulnerable groups and populations with higher exposures and identify environmental risks at specific contaminated sites with relatively low expenditure. The sensitivity of HBM methods moreover enables the elucidation of human metabolism and toxic mechanisms of the pollutants. So, HBM is a tool for scientists as well as for policy makers. Blood and urine are by far the most approved matrices. HBM can be done for most chemical substances which are in the focus of the worldwide discussion of environmental medicine. This especially applies for metals, PAH, phthalates, dioxins, pesticides, as well as for aromatic amines, perfluorinated chemicals, environmental tobacco smoke and volatile organic compounds. Protein adducts, especially Hb-adducts, as surrogates of DNA adducts measuring exposure as well as biochemical effect very specifically and sensitively are a still better means to estimate cancer risk than measuring genotoxic substances and their metabolites in human body fluids. Using very sophisticated but nevertheless routinely applicable analytical procedures Hb-adducts of alkylating agents, aromatic amines and nitro aromatic compounds are determined routinely today. To extend the spectrum of biochemical effect monitoring further methods should be elaborated which put up with cleavage and separation of the adducted protein molecules as a measure of sample preparation. This way all sites of adduction as well as further proteins, like serum albumin could be used for HBM. DNA-adducts indicate the mutagenicity of a chemical substance as well as an elevated cancer risk. DNA-adducts therefore would be ideal parameters for HBM. Though there are very sensitive techniques for DNA adduct monitoring like P32-postlabelling and immunological methods they lack specificity. For elucidating the mechanism of carcinogenesis and for a broad applicability and comparability in epidemiological studies analytical methods must be elaborated which are strictly specific for the chemical structure of the DNA-adduct. Current analytical possibilities however meet their borders. In HBM studies with exposure to genotoxic chemicals especially the measurement of DNA strand breaks in lymphocytes and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in white blood cells has become very popular. However, there is still a lack of well-established dose-response relations between occupational or environmental exposures and the induction of 8-OHdG or formation of strand breaks which limits the applicability of these markers. Most of the biomarkers used in population studies are covered by standard operating procedures (SOPs) as well as by internal and external quality assessment schemes. Therefore, HBM results from the leading laboratories worldwide are analytically reliable and comparable. Newly upcoming substances of environmental relevance like perfluorinated compounds can rapidly be assessed in body fluids because there are very powerful laboratories which are able to elaborate the analytical prerequisites in due time. On the other hand, it is getting more and more difficult for the laboratories to keep up with a progress in instrumental analyses. In spite of this it will pay to reach the ultimate summit of HBM because it is the only way to identify and quantify human exposure and risk, elucidate the mechanism of toxic effects and to ultimately decide if measures have to be taken to reduce exposure. Risk assessment and risk management without HBM lead to wrong risk estimates and cause inadequate measures. In some countries like in USA and in Germany, thousands of inhabitants are regularly investigated with respect to their internal exposure to a broad range of environmentally occurring substances. For the evaluation of HBM results the German HBM Commission elaborates reference- and HBM-values.
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            Identifying occupational carcinogens: an update from the IARC Monographs

            The recognition of occupational carcinogens is important for primary prevention, compensation and surveillance of exposed workers, as well as identifying causes of cancer in the general population. This study updates previously published lists of known occupational carcinogens while providing additional information on cancer type, exposure scenarios and routes, and discussing trends in the identification of carcinogens over time. Data were extracted from International Agency for Research on Cancer (IARC) Monographs covering the years 1971–2017, using specific criteria to ensure occupational relevance and provide high confidence in the causality of observed exposure-disease associations. Selected agents were substances, mixtures or types of radiation classified in IARC Group 1 with ‘sufficient evidence of carcinogenicity’ in humans from studies of exposed workers and evidence of occupational exposure documented in the pertinent monograph. The number of known occupational carcinogens has increased over time: 47 agents were identified as known occupational carcinogens in 2017 compared with 28 in 2004. These estimates are conservative and likely underestimate the number of carcinogenic agents present in workplaces. Exposure to these agents causes a wide range of cancers; cancers of the lung and other respiratory sites, followed by skin, account for the largest proportion. The dominant routes of exposure are inhalation and dermal contact. Important progress has been made in identifying occupational carcinogens; nevertheless, there is an ongoing need for research on the causes of work-related cancer. Most workplace exposures have not been evaluated for their carcinogenic potential due to inadequate epidemiologic evidence and a paucity of quantitative exposure data.
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              Global in-use stocks of the rare Earth elements: a first estimate.

              Even though rare earth metals are indispensible in modern technology, very little quantitative information other than combined rare earth oxide extraction is available on their life cycles. We have drawn upon published and unpublished information from China, Japan, the United States, and elsewhere to estimate flows into use and in-use stocks for 15 of the metals: La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, and Y. Here, we show that the combined flows into use comprised about 90 Gg in 2007; the highest for individual metals were ∼28 Gg Ce and ∼22 Gg La, the lowest were ∼0.16 Gg Tm and ∼0.15 Gg Lu. In-use stocks ranged from 144 Gg Ce to 0.2 Gg Tm; these stocks, if efficiently recycled, could provide a valuable supplement to geological stocks.
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                Author and article information

                Journal
                Med Lav
                Med Lav
                La Medicina del Lavoro
                Mattioli 1885 srl (Italy )
                0025-7818
                2532-1080
                2019
                26 August 2019
                : 110
                : 4
                : 251-270
                Affiliations
                [1 ]Section of Occupational Medicine, Department of Public Health, University of Naples Federico II, Naples, Italy
                [2 ]Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Italian Workers’ Compensation Authority (INAIL), Monte Porzio Catone, Rome, Italy
                Author notes
                Corrispondenza: Ivo Iavicoli, Section of Occupational Medicine, Department of Public Health, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy - E-mail: ivo.iavicoli@ 123456unina.it
                Article
                MDL-110-251
                10.23749/mdl.v110i4.8662
                7809994
                31475687
                b2e396d1-4881-442a-a84a-2caac0be9648
                Copyright: © 2020 ACTA BIO MEDICA SOCIETY OF MEDICINE AND NATURAL SCIENCES OF PARMA

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

                History
                : 05 July 2019
                : 15 July 2019
                Categories
                Original Article

                biological limit values,biological monitoring,chemical risk,exposure assessment,reference values

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