Elsevier

Toxicology Letters

Volume 192, Issue 1, 15 January 2010, Pages 45-49
Toxicology Letters

Biomarkers of exposure, effects and susceptibility in humans and their application in studies of interactions among metals in China

https://doi.org/10.1016/j.toxlet.2009.06.859Get rights and content

Abstract

Biomonitoring employs three categories of biomarkers: Biomarkers of exposure, i.e. measurements of metal concentrations in a compartment in the body reflecting external or internal exposure; Biomarkers of effects include early as well as clinical effects. Biomarkers of susceptibility indicate individuals with increased sensitivity of target molecules or metabolism causing increased target dose.

The three categories of biomarkers were used in studies of health effects of metal exposures in China. Adverse effects on the kidney tubules with increased levels of the effect biomarkers beta-2-microglobulin in urine (UB2M) and urinary N-acetyl-beta-d-glucosaminidase (UNAG) were found among Cd exposed population groups in China. Among persons exposed to Cd, occupationally or in the general environment, the level of Cd-induced metallothionein mRNA (MTmRNA) in peripheral lymphocytes appeared as a useful indicator of the ability of individuals to synthesize MT. Persons with low MTmRNA levels displayed higher biomarker values of renal tubular damage than persons with high levels of MTmRNA, at comparable levels of urinary Cd. Other studies demonstrated the importance of auto-antibodies against metallothionein in plasma (MTab) in modifying the response to Cd. Persons with high levels of MTab displayed tubular proteinuria at lower levels of urinary Cd than persons with low levels of MTab. Studies in two metal contaminated areas in China demonstrated clear interactions between Cd and inorganic arsenic. Combined exposure, with increased levels of As and Cd in urine, caused considerably higher biomarker values of renal tubular damage, measured as increased urinary levels of B2M or NAG, than each of the exposures alone.

Introduction

Biological monitoring may form a useful basis for human exposure assessment, but such assessment is usually based on environmental monitoring i.e. measurements of concentrations of chemical substances in various exposure media such as air, water and food. In the occupational setting, environmental monitoring may be performed as stationary sampling of industrial air and such monitoring may be preferred when source identification is important, whereas personal sampling will be chosen if an estimate of inhaled doses of individuals is desired (WHO/IPCS, 2000). An estimate of the total dose, taken up from different exposure routes may be obtained by adding measured exposures from the various exposure media, or even better, by biological monitoring, using an appropriate biomarker of exposure (see below). Biological monitoring or biomonitoring (BM) of human metal exposures has a long history. Lead levels in blood were first determined in 1927 (review by Aitio et al., 2007). Several meetings with discussions of BM were held in the 1970s and 1980s by the Scientific Committee on the Toxicology of Metals (SCTM) of ICOH (International Commission of Occupational Health) including one on Biological Monitoring of Toxic Metals (Clarkson et al., 1988). A series of ISBM (International Symposia on Biological Monitoring) organized by the Scientific Committee on Occupational Toxicology (SCOT) has later emerged and the 2007 Symposium in Beijing was a joint activity of SCOT and SCTM, both belonging to ICOH. A document concerning “Biomonitoring for Occupational Health Risk Asessment” by Manno et al. (this volume).

In modern biomonitoring programmes, three categories of biomarkers are used: biomarkers of exposure, biomarkers of effects and biomarkers of susceptibility. The present paper will present generally accepted definitions of the three categories of biomarkers and examples of the use of the various categories of biomarkers will be given. Studies aiming at finding biomarkers that may be useful in epidemiological studies of metal exposures were performed in China and will be used to indicate the potential usefulness of the three categories of biomarkers.

Section snippets

Conceptual considerations

The three categories of biomarkers have been defined as follows:

  • Biomarker of metal exposure: a biomarker that relates exposure to a metal to the level of that metal (or its metabolites, or the product of interaction with target molecules) in a body tissue or fluid (compartment) [Based on Aitio et al., 2007, IUPAC, 2004, WHO/IPCS, 1993].

  • Note: This definition includes measurements of interaction products between metals and target molecules, i.e. “target dose” (e.g. metal–enzyme complexes or

Studies in China employing biomarkers of exposure and effects in developing biomarkers of susceptibility

Exposures to cadmium in occupational and general environments are known to be related to risks of adverse effects on kidneys (Nordberg et al., 2007). Biomarkers of cadmium exposure and adverse effects have been established based on experimental and epidemiological evidence.

Studies in China of interactions between Cd and As, employing biomarkers of exposure and effect for assessing dose–reponse relationships

Biomarkers of Cd exposure and effects were the same as in the studies described previously in this review.

A number of biomarkers of As exposure are available (Fowler et al., 2007):

  • Arsenic in blood (BAs) is used only to a limited extent. Because of a very short half-life in blood, timing of blood sampling in relation to exposure is crucial.

  • As in Urine (UAs) can be determined either as total As or by speciation (hydride generation techniques or mass spectrometry) into inorganic As and its

Summary and general conclusions

Generally accepted definitions of the three categories of biomarkers were presented.

Biomarkers of exposure and effects of Cadmium were employed in the search for biomarkers of susceptibility.

Two potentially important biomarkers of susceptibility influencing the development of renal damage from cadmium were suggested, i.e. MT GE in PBL and MTAb in plasma.

Biomarkers of exposure to Cd and IAs and of their renal effects were used in studies of combined exposures in the general environment. There

Conflict of interest statement

The author declares no conflict of interests.

Acknowledgements

This article summarizes a presentation by the author at the International Symposium on Biological Monitoring in Occupational and Environmental Health, Beijing, 2007. The epidemiological studies in China were performed by Professor Taiyi Jin and his associates, Department of Occupational Health and Toxicology, School of Public Health, Fudan University, Shanghai, China; many of these studies were collaboration with the present author. Financial support was obtained by Swedish SAREC/SIDA and by

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