Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: a feasibility study of biomarkers

doi:10.1016/S0140-6736(00)04822-4

The Lancet

Volume 357, Issue 9269, 26 May 2001, Pages 1660-1669

https://doi.org/10.1016/S0140-6736(00)04822-4 Get rights and content

Summary

Background

Human exposure to chemicals is normally monitored by measurement of environmental pollutants in external media. We investigated whether biomarkers in adolescents can show exposure to, and health effects of, common environmental pollutants.

Methods

We recruited 200 17-year-old adolescents (120 girls) from a rural control area and from two suburbs polluted by a lead smelter and two waste incinerators. We measured biomarkers of exposure and of effect in blood and urine samples, and obtained questionnaire data. School doctors measured testicular volume and staged sexual maturation.

Findings

Internal exposure was mostly within current standards. Concentrations of lead and cadmium in blood, PCBs (polychlorinated biphenyls) and dioxin-like compounds in serum samples, and metabolites of VOCs (volatile organic compounds) in urine were higher in one or both suburbs than in the control area. Children who lived near the waste incinerators matured sexually at an older age than others, and testicular volume was smaller in boys from the suburbs than in controls. Biomarkers of glomerular or tubular renal dysfunction in individuals were positively correlated with blood lead. Biomarkers of DNA damage were positively correlated with urinary metabolites of PAHs (polycyclic aromatic hydrocarbons) and VOCs.

Interpretation

Biomarkers can be used to detect environmental exposure to pollutants and measure their biological effects before overt disease develops. Our findings suggest that current environmental standards are insufficient to avoid measurable biological effects.

Introduction

People worldwide are exposed to many environmental pollutants, which are usually monitored by measurements in air, food, water, soil, or dust. Extrapolation from these data to assess the total internal exposure of human beings or to the possible health effects is uncertain.¹ People are exposed via different routes. Variability between individuals in absorption, distribution, metabolism, and excretion of xenobiotics is huge. Several chemicals can act on the same target organs. Diseases caused by chronic exposure to low concentrations of pollutants might become clinically evident only after a long period of time. Concentrations of pollutants or their metabolites in blood, urine, or tissues show current or lifetime exposure via all routes. Biomarkers of exposure are more directly associated with biomarkers of effects than are measurements of pollutants in external media, and provide better estimates of health risk before onset of disease.²

Exposure to chlorinated pesticides has been compared between women aged 50–65 years in rural areas and in suburbs: serum-sample concentrations of pentachlorophenol, lindane, and active p,p′-DDT (dichlorodiphenyl-trichloroethane) and its inactive metabolite p,p′-DDE were significantly higher in rural areas than in suburbs (100 women per area), but the opposite was noted for hexachlorobenzene (Department of Welfare, Health and Equal Opportunities, Ministry of the Flemish Community, Brussels, 2000).

We have therefore investigated whether biomarkers can reveal exposure and early health effects in relation to four main classes of environmental pollutants: heavy metals, polychlorinated biphenyls (PCBs), volatile organic compounds (VOCs), and polycyclic aromatic hydrocarbons (PAHs). We chose 17-year-old adolescents as our target population, because in a society with a life expectancy of more than 74 years, biomarkers in young people show recent exposure, even for cumulative toxins such as heavy metals,³ polychlorinated biphenyls,4, 5 or dioxins.⁴ Moreover, in Belgium, school attendance is compulsory until age 18 years and school doctors routinely examine adolescents. Hence, our study benefited from professional expertise and infrastructure.

Section snippets

Geographical areas

The suburbs Hoboken and Wilrijk are 11–13 km south-east of the chemical industry in the seaport of Antwerp.⁶ We selected them for our study area because they included a large non-ferrous smelter,7, 8 two waste incinerators,⁹ a crematory,⁹ a printing works, and other various industries. Both suburbs are crossed by motorways that carry over 80 000 vehicles per day.⁶ In 1998, the mean air concentrations of benzene, toluene, and ethylbenzene were 3·2, 13·0, and 3·6 μg/m³, respectively (Vlaamse

Participants

524 adolescents, born in 1980–83 were eligible. 169 children were excluded: seven because they had not lived all their lives in the study areas, and 162 because the sex quota by area had already been filled. Of 355 invited youngsters, 207 (58%) volunteered to take part. We did not examine seven adolescents: three had recently moved out of the study area, two were unavailable because of illness, and two were away travelling.

The 200 adolescents included 120 girls (60%), none of whom were

Discussion

In adolescents, biomarkers were sensitive enough to detect significant geographical gradients in common environmental pollutants, in their metabolites, and in their biological effects. Across individual teenagers, dose-effect and dose-response curves were established, which were prespecified in our protocol on the basis of experimental data,21, 22, 31 hypotheses,31, 32, 33 or observations mostly made at high levels of occupational1, 18, 20, 29, 34 or accidental³⁵ exposure to pollutants. We also

References (53)

HA Roels et al.
Exposure to lead by the oral and the pulmonary routes of children living in the vicinity of a primary lead smelter
Environ Res
(1980)
HA Roels et al.
Lead and cadmium absorption among children near a nonferrous metal plant: a follow-up study of a test case
Environ Res
(1978)
P Van Hummelen et al.
Biological markers in PAH exposed workers and controls
Mutat Res
(1993)
JP Buchet et al.
Renal effects of cadmium body burden of the general population
Lancet
(1990)
F Van Goethem et al.
Comparative evaluation of the in vitro micronucleus test and the alkaline single cell electrophoresis assay for the detection of DNA damaging agents: genotoxic effects of cobalt powder, tungsten carbide and cobalt-tungsten carbide
Mutat Res
(1997)
van ZeelandAA et al.
8–hydroxydeoxyguanosine in DNA from leukocytes of healthy adults: relationship with cigarette smoking, environmental tobacco smoke, alcohol and coffee consumption
Mutat Res
(1999)
A Brouwer et al.
Functional aspects of development toxicity of polyhalogenated aromatic-hydrocarbons in experimental animals and human infants
Eur J Pharmacol
(1995)
DH Phillips
Polycyclic aromatic hydrocarbons in the diet
Mutat Res
(1999)
AM Bernard et al.
Renal effects in children living in the vinicity of a lead smelter
Environ Res
(1995)
R Clapp et al.
Where the boys aren't: dioxin and the sex ratio
Lancet
(2000)

C Koopman-Esseboom et al.

PCB and dioxin levels in plasma and human milk of 418 Dutch women and their infants: predictive value of PCB congener levels in maternal plasma for fetal and infant's exposure to PCBs and dioxins

Chemosphere

(1994)

P Mocarelli et al.

Paternal concentrations of dioxin and sex ratio of offspring

Lancet

(2000)

RR Lauwerys et al.

Industrial chemical exposure: guidelines for biological monitoring

(1993)

JA Timbrell et al.

Biomarkers in toxicology: new uses for some old molecules?

Biomarkers

(1996)

M Abdulla et al.

New aspects on the distribution and metabolism of essential trace elements after dietary exposure to toxic metals

Biol Trace Elem Res

(1990)

A Bernard et al.

Food contamination by PCBs and dioxins: an isolated episode in Belgium is unlikely to have affected public health

Nature

(1999)

RD Kimbrough

Polychlorinated biphenyls (PCBs) and human health: an update

Crit Rev Toxicol

(1995)

G Schoeters et al.

Studie van de gezondheidsaspecten en gezondheidsrisico's ten gevolge van de milieuverontreininging in de Neerlandwijk te Wilrijk

(1998)

Statistich nieuws: meetresultaten dioxinedeposities 2000 VMM

WA Marshall et al.

Variations in the pattern of pubertal changes in girls

Arch Dis Child

(1969)

WA Marshall et al.

Variations in the pattern of pubertal changes in boys

Arch Dis Child

(1970)

V Dörnberger et al.

Vergleichende Volumetrie des menschlichen Hodens unter besonderer Berücksichtigung der Hodensonographie, Praderorchidometer, Schirrenzirkel und Schublehre

Andrologia

(1987)

JA Staessen et al.

Life style as a determinant of blood pressure in the general population

Am J Hypertens

(1994)

BC Breedveld et al.

Nederlandse Voedingsmiddelentabel

(1996)

V Haufroid et al.

Urinary cotinine as a tobacco-smoke exposure index: a mini-review

Int Arch Occup Environ Health

(1998)

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Several metals have nephrotoxic properties. In this chapter we discuss various methods for assessing nephrotoxicity, different forms of proteinuria, and methods of estimating the glomerular filtration rate. Metals may affect renal glomeruli, resulting in a decreased glomerular filtration rate, sometimes associated with massive albuminuria. Effects on renal tubular function are more common, affecting the reabsorption of minerals, glucose, amino acids, and low molecular weight proteins from filtered primary urine. Various biomarkers, especially proteinuria, are also discussed. The most important nephrotoxic metals are lead, cadmium, and mercury. Acute nephrotoxic effects are sometimes seen, especially in suicide attempts or as side effects when metals (e.g., gold, platinum, lithium and antimony) are used in treatment of certain diseases. Long-term exposure is more common, e.g., via diet, drinking water, or occupational exposure. For example, long-term exposure to cadmium sometimes causes chronic kidney disease, and in rare cases the development of end-stage renal disease with uremia. Lithium used for treatment of mano-depressive disorders often cause polyuria and sometimes chronic kidney disease.
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The Flemish Environment and Health Studies (FLEHS) are human biomonitoring surveys running in Flanders since 1999. Additionally to biomarkers of exposure, markers of genotoxicity and oxidative stress have been measured, including the alkaline comet and micronucleus assay in peripheral whole blood cells, and urinary concentrations of 8-oxo-2′-deoxyguanosine (8-oxodG).
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The biomarkers were measured in 2283 adolescents in the age range of 14–18 years. Exposure to polycyclic aromatic hydrocarbons [1-hydroxypyrene (1-OHP)], benzene (tt’-muconic acid), metals (arsenic, cadmium, copper, nickel, thallium, lead, chromium), persistent organochlorines and phthalates were assessed in blood or urine. Furthermore, outdoor air levels of particulate matter (PM₁₀ and PM_2.5) at the residences of the youngsters were calculated. Pooled statistical analysis was done using mixed models. Study-specific differences in the genotoxicity markers and in the strength/direction of the association were accounted for. This was done by incorporating the random factor ‘study’ and a random study slope (if possible). The exposure markers were centered around the study-specific mean in order to correct for protocol changes over time.
A significant association was observed for the urinary oxidative stress marker 8-oxodG, which was positively associated with 1-OHP (5% increase for doubling of 1-OHP levels, p = 0.001), and with urinary copper (26% increase for doubling of copper levels, p = 0.001), a metal involved in the Fenton reaction in biological systems. 8-oxodG was also associated with the sum of the metabolites of the phthalate di(2-ethylhexyl) phthalate (DEHP) (3% increase for doubling of the DEHP levels, p = 0.02). For those associations, data pooling increased the statistical power. However, some of the associations in the individual surveys, were not confirmed in the pooled analysis (such as comet assay and 8-oxodG vs. atmospheric PM; and 8-oxodG vs. urinary nickel). This may be due to inconsistencies in exposure-effect relations and/or variations in the pollutant mix over time and regions.
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Polycyclic aromatic hydrocarbons (PAHs) exposure has been shown to be a risk factor for many diseases. However, studies on the association between PAHs exposure and kidney disease are limited. The aim of this study was to explore the association between urinary PAHs and albuminuria based on a national representative sample from the general U.S. population.
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ArticlesRenal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: a feasibility study of biomarkers

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Geographical areas

Participants

Discussion

Environ Res

Environ Res

Mutat Res

Lancet

Mutat Res

Mutat Res

Eur J Pharmacol

Mutat Res

Environ Res

Lancet

Chemosphere

Lancet

Industrial chemical exposure: guidelines for biological monitoring

Biomarkers in toxicology: new uses for some old molecules?

Biomarkers

New aspects on the distribution and metabolism of essential trace elements after dietary exposure to toxic metals

Biol Trace Elem Res

Food contamination by PCBs and dioxins: an isolated episode in Belgium is unlikely to have affected public health

Nature

Polychlorinated biphenyls (PCBs) and human health: an update

Crit Rev Toxicol

Studie van de gezondheidsaspecten en gezondheidsrisico's ten gevolge van de milieuverontreininging in de Neerlandwijk te Wilrijk

Statistich nieuws: meetresultaten dioxinedeposities 2000 VMM

Variations in the pattern of pubertal changes in girls

Arch Dis Child

Variations in the pattern of pubertal changes in boys

Arch Dis Child

Vergleichende Volumetrie des menschlichen Hodens unter besonderer Berücksichtigung der Hodensonographie, Praderorchidometer, Schirrenzirkel und Schublehre

Andrologia

Life style as a determinant of blood pressure in the general population

Am J Hypertens

Nederlandse Voedingsmiddelentabel

Urinary cotinine as a tobacco-smoke exposure index: a mini-review

Int Arch Occup Environ Health

Articles
Renal function, cytogenetic measurements, and sexual development in adolescents in relation to environmental pollutants: a feasibility study of biomarkers