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Revised and new reference values for arsenic, cadmium, lead and mercury in blood or urine of children. Basis for validation of human biomonitoring data in environmental medicine
ARTICLE IN PRESS
Int. J. Hyg. Environ.-Health 209 (2006) 301–305 www.elsevier.de/ijheh
Revised and new reference values for arsenic, cadmium, lead, and mercury in blood or urine of children: Basis for validation of human biomonitoring data in environmental medicine Michael Wilhelma, Christine Schulzb,, Michael Schwenkc,1 a
Department of Hygiene, Social and Environmental Medicine, Ruhr-University Bochum, Bochum, Germany Federal Environmental Agency, Berlin, Germany c Landesgesundheitsamt Stuttgart, Germany b
Abstract Reference values for environmental pollutants in the German population are established continuously by the Human Biomonitoring Commission of the German Federal Environmental Agency. The reference values (defined as 95th percentile) are usually derived from results of the German Environmental Surveys (GerES). However, current reference values for children are lacking since GerES II conducted in 1990/92 and additionally the first German Environmental Survey on Children (GerES IV) will not be finished until the end of 2006. As an interim solution, the commission derived in 2005 reference values for children aged 6–12 years from a survey performed in south-west Germany in 2002/03 (508 children) and the pilot study for GerES IV 2001/2002 (252 children). A new reference value of 15 mg/l for children was derived for arsenic in urine. The reference values for cadmium in whole blood (0.5 mg/l) and for cadmium in urine (0.5 mg/l) were confirmed. The following reference values were lowered: for lead in blood from 60 to 50 mg/l, for mercury in whole blood from 1.5 to 1.0 mg/l and for mercury in urine from 1.4 to 0.7 mg/l.
Keywords: Human biomonitoring; Reference values; Blood; Urine; Arsenic; Cadmium; Lead; Mercury; Children; Environmental medicine; Germany
Introduction Human biomonitoring is an important tool in environmental medicine to assess and evaluate the level of internal exposure of the general population, population groups and individuals to environmental pollutants. In Germany, the Human Biomonitoring Commission of the German Federal Environmental Agency was established in 1992 to develop scientifically based criteria for Corresponding author. Tel.: +49 30 89035465; fax: +49 30 89031830. E-mail address: [email protected] (C. Schulz). 1 Retired.
1438-4639/$ - see front matter doi:10.1016/j.ijheh.2006.01.004
the application of human biomonitoring. The working principles and the working procedures of the commission have been summarized by Ewers et al. (1999). Reference values must be revised periodically according to changes in the exposure of general population to environmental pollutants. New and revised reference values were reported for persistent organic pollutants (Wilhelm et al., 2003), for trace elements (Wilhelm et al., 2004) and for metabolites of pyrethroid and organophosphorous insecticides (Heudorf et al., 2006). In recent years, concerns have been raised that children may be more susceptible to toxic exposure than adults (Au, 2002). Therefore human biomonitoring needs to be focused on exposure assessment of children
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to environmental contaminants. The reference values are usually derived from the German Environmental Surveys (GerES) (Seifert et al., 2000; Becker et al., 2002, 2003, 2006). However, current reference values for children in Germany are lacking since the GerES II in 1990/92 and additionally the first German Environmental Survey especially designed for children (GerES IV) will not be finished until the end of 2006 (Schulz et al., 2002, http://www.umweltbundesamt.de/survey-e/ pub/BriefDescription_January2005_2.pdf, date: February 15, 2006). Therefore, the commission derived reference values for children aged 6–12 years from a survey performed in south-west Germany 2002/03 and the pilot study for GerES IV 2001/2002 (Human Biomonitoring Commission, 2005a; see also http:// www.umweltbundesamt.de/uba-info-daten-e/daten-e/ monitor/pub.htm, no. 50, date: February 15, 2006). Though both studies are not representative for the German population, they provide at present the best available data basis for deriving reference values for arsenic, cadmium, lead, and mercury in blood or urine of children.
General remarks The reference value is defined as the 95th percentile of the distribution of concentrations of a specific compound or element in a body fluid of a reference population (Ewers et al., 1999). Reference values for pollutants in urine are expressed as mg/l urine (and no longer as mg/g creatinine). In line with the WHO recommendations (WHO, 1996), the commission decided when deriving reference values to include only urine samples with creatinine levels in the range between 0.3 and 3.0 g/l. For human biomonitoring in environmental medicine it is recommended that in individual cases of values exceeding the reference value, a repeated sampling should be performed and care should be taken that the urine exhibits a normal dilution, i.e., a creatinine content between 0.5 and 2.5 g/l (Human Biomonitoring Commission, 2005b). When applying the reference values an analytical uncertainty of 720% should be considered.
Data basis The data basis is comprised of 2 studies. The survey performed in south-west Germany is a repeated crosssectional study started in 1992 (Landesgesundheitsamt Baden-Wu¨rttemberg, 2002, 2005). Each winter (October–March) school children (4th grade, age 9–11 years) from well-defined urban and rural areas are studied during this ‘‘Sentinel Health Departments of BadenWu¨rttemberg’’ project. Human biomonitoring comprises arsenic, some metals and persistent organic pollutants. Details on sampling of the study population,
questionnaire, sampling for analysis, analysis, statistical methods are given in a report (Landesgesundheitsamt Baden-Wu¨rttemberg, 2002). GerES are population-representative studies (Seifert et al., 2000). In the pilot study for GerES IV, the survey on children, children and adolescents aged 0–17 years were selected at random at four study areas (urban vs. rural and east vs. west Germany). The survey was conducted between March 2001 and March 2002 (Seifert et al., 2002, http://www.umweltbundesamt.de/survey-e/ pub/BriefDescription_January2005_2.pdf, date: February 15, 2006). The methods used (sampling of study population, questionnaire, sampling for analysis, analysis, statistical data treatment) are described in the final report ‘‘Pre-test for the Environmental Survey for Children and Adolescents’’ (Umweltbundesamt, 2004, http://www.umweltbundesamt.de/survey/pub/Pilotstudie_ 2001–02.htm, date: February 15, 2006). For an update of the reference values derived earlier for 6–12-year-old children, only the results for this age group are taken from the GerES IV pilot study. To analyze arsenic, cadmium and mercury in urine, spontaneous urine samples were taken in the ‘‘Sentinel Health Departments in Baden-Wu¨rttemberg’’ project, whereas morning urine samples were used in the GerES IV pilot study. The comparison of creatinine concentrations in spontaneous urine and morning urine did not show substantial differences. Therefore, it seemed to be acceptable to make use of the results of both methods to determine reference values.
Arsenic in urine Arsenic was determined with the hydride batch method. The results on arsenic levels in urine of both surveys are summarized in Table 1. Recent and frequent fish consumption led to higher arsenic values in urine (Human Biomonitoring Commission, 2003). As expected the arsenic concentrations in urine were mainly influenced by the recent fish consumption (see Table 1). Clear trends could be observed for the arsenic levels in urine of children over the last years in Germany. For the first time, a reference value for arsenic in urine of children is derived. The reference value of 15 mg/l is set for children aged 6–12 years who had no fish consumption during the preceding 48 h before sampling. For human biomonitoring of arsenic in environmental medicine it is recommended that any fish consumption during the last 48 h before sampling is avoided. Other potential sources than fish consumption causing higher levels of arsenic in urine could be local supply of drinking water contaminated with arsenic, mineral water, also that for medical treatment, arsenic-containing drugs or exposure to arsenic-contaminated dust or soil, e.g. from industrial waste.
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Table 1. Concentrations of arsenic, cadmium and mercury in urine (mg/l) as well as of cadmium, lead, and mercury in blood (mg/l) of children from the ‘‘Sentinel Health Departments of Baden-Wu¨rttemberg’’ project 2002/03 (BW-EHS) (Landesgesundheitsamt, 2005) and the pilot study for the German Environmental Survey on Children 2001/02 (GerES IV pilot study) (http:// www.umweltbundesamt.de/survey/pub/Bericht_Pretest-3.pdf, Schulz et al., 2002) and reference values for children aged 6-12 years (right colums; according to Human Biomonitoring Commission, 2005a) Substance/Groups
N
NoLOQ
P 50
P 95
Arsenic in urine (lg/l) All BW-EHS (age 9–11 years) All GerES IV pilot study (age 6–12 years)
508 252
0 5
4.6 4.8
19.4 13.9
No fish consumption during preceding 48 h BW-EHS GerES IV pilot study
428 197
0 5
4.4 4.5
13.4 11.4
Fish consumption during preceding 48 h BW-EHS Ger ES IV pilot study
62 46
0 0
7.8 7.0
39.6 34.3
Cadmium in urine (lg/l) Non-smokers GerES IV pilot study (6–12 years)
248
74
0.10
0.38
Mercury in urine (lg/l) All BW-EHS (age 9–11 years) All GerES IV pilot study (age 6–12 years)
510 252
330 46
o 0.2 0.2
1.2 0.852b
Without teeth with amalgam fillings BW-EHS GerES IV pilot study
406 216
264 41
o 0.2 0.2
0.55 0.6
With teeth with amalgam fillings BW-EHS GerES IV pilot study
66 33
0 4
0.4 0.4
3.7 2.6
Cadmium in blood (lg/l) Non-smokers BW-EHS (age 9–11 years) GerES IV pilot study (age 6–12 years)
430 231
43 128
0.25 o 0.12
0.49 0.32
0.46–0.51b 0.23–0.38c
Lead in blood (lg/l) All BW-EHS (age 9–11 years) All GerES IV pilot study (age 6-12 years)
430 234
42 2
20.7 24
37.9 52
37.2–41.5b 46–55b
Mercury in blood (lg/l) All GerES IV pilot study (age 6-12 years)
233
73
0.20
1.00
Consumption of fish p 3 times/month Consumption of fish43 times/month
166 67
58 15
0.20 0.30
0.80 1.56
CI 95 PP
Reference valuea
15.0 lg/l 13.2–16.5b 12.1–16.8b
0.5 lg/l 0.31–0.45c 0.36–0.52b
0.7 lg/l 0.40–0.49b 0.40–0.77c
0.5 g/l
50 lg/l
0.6–1.0c
1.0 lg/l
N ¼ number of samples; LOQ ¼ limit of quantification; valuesoLOQ were set to LOQ/2; P50, P 95 ¼ percentiles; CI 95 PP ¼ 95% confidence interval for P 95 of the population percentile. Urine samples with creatinine levelso0.3 or43.0 mg/l are excluded when deriving the reference values. a An analytical uncertainty of 720% has to be taken into account when using the reference values. b Parametric procedure. c Bootstrapping procedure.
Cadmium in blood and urine The results on cadmium levels in blood of both surveys are summarized in Table 1. Cadmium levels in urine were only available from the GerES IV pilot study (Table 1). The cadmium concentrations in blood and
urine of adults were mainly influenced by tobacco smoke exposure (Human Biomonitoring Commission, 1998), therefore the reference values for cadmium in blood and urine were set for non-smoking persons. In contrast to adults no influence of tobacco smoke exposure on cadmium in blood and urine of children was observed.
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Compared with the former GerES II (1990/92) a decline of cadmium levels in urine and blood of children could not be detected clearly. Thus the former reference values of 0.5 mg/l blood and 0.5 mg/l urine established by the commission in 1998 were maintained. Increased cadmium levels in urine and blood can be due to active tobacco smoking, uptake with food, or intake of cadmium-containing dust and soil from industrial waste (Human Biomonitoring Commission, 2005a).
Lead in blood The results on lead levels in blood of both surveys are summarized in Table 1. Compared to the results of former surveys there is a decrease of the mean blood lead concentration of children. Thus, the reference values for lead in blood of 60 mg/l (Human Biomonitoring Commission, 1996) established by the Commission in 1996 was lowered to 50 mg/l for children aged 6-12 years. Sources or pathways for elevated lead content in blood could be lead-contaminated drinking water (if water pipes in old building are still containing lead), frequent eating of acid food from dishes with leadcontaining glaze or hot drinks from ceramics, exposure to metallic lead (e.g. New Year’s Eve custom in Germany of telling fortunes by the shapes made by molten lead dropped into cold water), exposure to leadcontaining ammunition, and the uptake of dust or soil contaminated with lead, e.g. from industrial waste (Human Biomonitoring Commission, 2005a).
number of amalgam fillings. Compared to former studies mercury levels in urine had decreased. Thus the reference value of 1.4 mg/l established by the commission in 1999 was lowered to 0.7 mg/l for children aged 6–12 years without teeth with amalgam fillings. Sources for increased mercury levels in urine could be teeth with amalgam fillings, frequent consumption of fish and seafood (both crustaceans and molluscs), the uptake of mercury vapors in the home due to broken clinical thermometers containing liquid mercury, or mercurycontaining drugs and bleaching ointments (Human Biomonitoring Commission, 2005a).
Recommendations in cases of values exceeding the reference values A repeat measurement should be performed in cases of concentrations exceeding the reference value. If reliable (checked several times) measurements show a value above the reference value, they should induce an environmental medicine-based search for sources. Such search should be carried out in a proportionate way. It must be emphasized that reference values are statistically derived and do not represent toxicologically derived biological exposure limits. Thus, they cannot be used for health-related evaluation of human biomonitoring data. Nevertheless, the reference values permit to assess the exposure of individuals or population groups compared to the ubiquitous background exposure.
Mercury in blood and urine Mercury in blood reflects the internal exposure resulting from organic and inorganic mercury (Human Biomonitoring Commission, 1999). Mercury blood levels were only available from the GerES IV pilot study (Table 1). Compared to the levels observed in GerES II (1990/92) there was a marked decrease of mercury blood levels for children. Consequently, the currently existing reference value of 1.5 mg/l (Human Biomonitoring Commission, 1999) was lowered to 1.0 mg/l for children consuming fish up to three times per months. Elevated mercury levels of blood may be caused by frequent consumption of fish and seafood (both crustaceans and molluscs), by uptake of mercury vapors in the home due to broken clinical thermometers containing liquid mercury, or mercury-containing drugs (Human Biomonitoring Commission, 2005a). Mercury in urine reflects the exposure to inorganic mercury (Human Biomonitoring Commission, 1999). The results on mercury levels in urine of both surveys are summarized in Table 1. As expected the mercury concentrations in urine were mainly influenced by amalgam fillings (see Table 1). The levels increased with
Further perspectives As soon as data from the German Environmental Survey for Children (GerES IV) are available the Human Biomonitoring Commission will provide revised or new reference values for environmental pollutants for children.
Acknowledgements This report is based on a consensus paper of the Human Biomonitoring Commission. The authors thank the other members of the commission J. Angerer, W. Butte, R. Eckard, U. Ewers, B. Heinzow, U. Heudorf, A. Kappos, and H. Kruse for their co-operation.
References Au, W.W., 2002. Susceptibility of children to environmental toxic substances. Int. J. Hyg. Environ. Health 205, 501–503.
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Becker, K., Kaus, S., Krause, C., Lepom, P., Schulz, C., Seiwert, M., Seifert, B., 2002. German Environmental Survey 1998 (GerES III): environmental pollutants in blood of the German population. Int. J. Hyg. Environ. Health 205, 297–308. Becker, K., Schulz, C., Kaus, S., Seiwert, M., Seifert, B., 2003. German Environmental Survey 1998 (GerES III): environmental pollutants in urine of the German population. Int. J. Hyg. Environ. Health 206, 15–24. Becker, K., Seiwert, M., Angerer, J., Kolossa-Gehring, M., Hoppe, H.-W., Ball, M., Schulz, C., Thumulla, J., Seifert, B., 2006. GerES IV Pilot study: assessment of the exposure of German children to organophosphorous and pyrethroid pesticides. Int. J. Hyg. Environ. Health 209, 221–233. Ewers, U., Krause, C., Schulz, C., Wilhelm, M., 1999. Reference values and human biological monitoring values for environmental toxins. Int. Arch. Occup. Environ. Health 72, 255–260. Heudorf, U., Butte, W., Schulz, C., Angerer, J., 2006. Reference values for metabolites of pyrethroid and organophosphorous insecticides in urine for human biomonitoring in environmental medicine. Int. J. Hyg. Environ. Health 209, 293–299. Human Biomonitoring Commission (Kommission ‘‘HumanBiomonitoring’’ des Umweltbundesamtes), 1996. Stoffmonographie Blei – Referenz- und Human-BiomonitoringWerte (HBM). Bekanntmachung des Instituts fu¨r Wasser-, Boden- und Lufthygiene des Umweltbundesamtes. Bundesgesundhbl 39, 236–241. Human Biomonitoring Commission (Kommission ‘‘HumanBiomonitoring’’ des Umweltbundesamtes), 1998. Stoffmonographie Cadmium – Referenz- und Human-Biomonitoring-Werte (HBM). Bekanntmachung des Instituts fu¨r Wasser-, Boden- und Lufthygiene des Umweltbundesamtes. Bundesgesundhbl 41, 218–226. Human Biomonitoring Commission (Kommission ‘‘HumanBiomonitoring’’ des Umweltbundesamtes), 1999. Stoffmonographie Quecksilber – Referenz- und Human-BiomonitoringWerte (HBM). Bekanntmachung des Instituts fu¨r Wasser-, Boden- und Lufthygiene des Umweltbundesamtes. Bundesgesundheitsbl. Gesundheitsforsch. Gesundheitsschutz 42, 522–532 see: http://www.umweltdaten.de/daten-e/monitor/ HG-MONO_engl.pdf, no 18, date: February 15, 2006. Human Biomonitoring Commission (Kommission ‘‘HumanBiomonitoring’’ des Umweltbundesamtes), 2003. Stoffmonographie Arsen – Referenzwert fu¨r Urin – Stellungnahme der Kommission ‘‘Human-Biomonitoring’’ des Umweltbundesamtes. Bundesgesundheitsbl. Gesundheitsforsch. Gesundheitsschutz 46, 1098–1106 see: http://www. umweltdaten.de/daten-e/monitor/39e.pdf, no 39, date: February 15, 2006.
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Human Biomonitoring Commission (Kommission ‘‘HumanBiomonitoring’’ des Umweltbundesamtes), 2005a. Neue und aktualisierte Referenzwerte fu¨r Schadstoffgehalte in Blut und Urin von Kindern – Arsen, Blei, Cadmium und Quecksilber. Bundesgesundheitsbl. Gesundheitsforsch. Gesundheitsschutz 48, 1308–1312. Human Biomonitoring Commission (Kommission ‘‘HumanBiomonitoring’’ des Umweltbundesamtes), 2005b. Normierung von Stoffgehalten im Urin- Kreatinin. Bundesgesundheitsbl. Gesundheitsforsch. Gesundheitsschutz 48, 616–618. Landesgesundheitsamt Baden-Wu¨rttemberg, 2002. Beobachtungsgesundheitsa¨mter; Belastungs- und Wirkungsmonitoring. Untersuchung 2000/01. Ergebnisse und Bewertung (Heft 2002/1 und Anhang Heft 2002/2). Landesgesundheitsamt Baden-Wu¨rttemberg, Stuttgart. Landesgesundheitsamt Baden-Wu¨rttemberg, 2005. Beobachtungsgesundheitsa¨mter; Belastungs- und Wirkungsmonitoring. Untersuchung 2002/03. Ergebnisse und Bewertung (Heft 2005/1 und Anhang Heft 2005/1). Landesgesundheitsamt Baden-Wu¨rttemberg, Stuttgart. Schulz, C., Becker, K., Seiwert, M., 2002. Kinder-UmweltSurvey. Gesundheitswesen 64 (Sonderheft 1), S69–S79. Seifert, B., Becker, K., Helm, D., Krause, C., Schulz, C., Seiwert, M., 2000. The German Environmental Survey 1990/92 (GerES II): reference concentrations of selected environmental pollutants in blood, urine, hair, house dust, drinking water, and indoor air. J. Exp. Anal. Environ. Epidemiol. 10, 552–565. Seifert, B., Becker, K., Kaus, S., Schulz, C., Krause, C., Seiwert, M., 2002. The German Environmental Survey for children and teenagers (GerES IV): first results of the pilot study. In: Abstracts of the 12th Annual Conference of ISEA 2002. Vancouver, Canada, August 11–15, 2002, p. 129. Umweltbundesamt, 2004. Abschlussbericht des UFOPLANVorhabens ‘‘Pretest zum Umwelt-Survey fu¨r Kinder und Jugendliche’’ FKZ 299 62 263/02. Umweltbundesamt, Berlin. WHO, 1996. Biological Monitoring of Chemical Exposure in the Workplace, Vol. 1. World Health Organization, Geneva. Wilhelm, M., Ewers, U., Schulz, C., 2003. Revised and new reference values for some persistent organic pollutants (POPs) in blood for human biomonitoring in environmental medicine. Int. J. Hyg. Environ. Health 206, 223–229. Wilhelm, M., Ewers, U., Schulz, C., 2004. Revised and new reference values for some trace elements in blood and urine for human biomonitoring in environmental medicine. Int. J. Hyg. Environ. Health 207, 69–73.
Int. J. Hyg. Environ.-Health 209 (2006) 301–305 www.elsevier.de/ijheh
Revised and new reference values for arsenic, cadmium, lead, and mercury in blood or urine of children: Basis for validation of human biomonitoring data in environmental medicine Michael Wilhelma, Christine Schulzb,, Michael Schwenkc,1 a
Department of Hygiene, Social and Environmental Medicine, Ruhr-University Bochum, Bochum, Germany Federal Environmental Agency, Berlin, Germany c Landesgesundheitsamt Stuttgart, Germany b
Abstract Reference values for environmental pollutants in the German population are established continuously by the Human Biomonitoring Commission of the German Federal Environmental Agency. The reference values (defined as 95th percentile) are usually derived from results of the German Environmental Surveys (GerES). However, current reference values for children are lacking since GerES II conducted in 1990/92 and additionally the first German Environmental Survey on Children (GerES IV) will not be finished until the end of 2006. As an interim solution, the commission derived in 2005 reference values for children aged 6–12 years from a survey performed in south-west Germany in 2002/03 (508 children) and the pilot study for GerES IV 2001/2002 (252 children). A new reference value of 15 mg/l for children was derived for arsenic in urine. The reference values for cadmium in whole blood (0.5 mg/l) and for cadmium in urine (0.5 mg/l) were confirmed. The following reference values were lowered: for lead in blood from 60 to 50 mg/l, for mercury in whole blood from 1.5 to 1.0 mg/l and for mercury in urine from 1.4 to 0.7 mg/l.
Keywords: Human biomonitoring; Reference values; Blood; Urine; Arsenic; Cadmium; Lead; Mercury; Children; Environmental medicine; Germany
Introduction Human biomonitoring is an important tool in environmental medicine to assess and evaluate the level of internal exposure of the general population, population groups and individuals to environmental pollutants. In Germany, the Human Biomonitoring Commission of the German Federal Environmental Agency was established in 1992 to develop scientifically based criteria for Corresponding author. Tel.: +49 30 89035465; fax: +49 30 89031830. E-mail address: [email protected] (C. Schulz). 1 Retired.
1438-4639/$ - see front matter doi:10.1016/j.ijheh.2006.01.004
the application of human biomonitoring. The working principles and the working procedures of the commission have been summarized by Ewers et al. (1999). Reference values must be revised periodically according to changes in the exposure of general population to environmental pollutants. New and revised reference values were reported for persistent organic pollutants (Wilhelm et al., 2003), for trace elements (Wilhelm et al., 2004) and for metabolites of pyrethroid and organophosphorous insecticides (Heudorf et al., 2006). In recent years, concerns have been raised that children may be more susceptible to toxic exposure than adults (Au, 2002). Therefore human biomonitoring needs to be focused on exposure assessment of children
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to environmental contaminants. The reference values are usually derived from the German Environmental Surveys (GerES) (Seifert et al., 2000; Becker et al., 2002, 2003, 2006). However, current reference values for children in Germany are lacking since the GerES II in 1990/92 and additionally the first German Environmental Survey especially designed for children (GerES IV) will not be finished until the end of 2006 (Schulz et al., 2002, http://www.umweltbundesamt.de/survey-e/ pub/BriefDescription_January2005_2.pdf, date: February 15, 2006). Therefore, the commission derived reference values for children aged 6–12 years from a survey performed in south-west Germany 2002/03 and the pilot study for GerES IV 2001/2002 (Human Biomonitoring Commission, 2005a; see also http:// www.umweltbundesamt.de/uba-info-daten-e/daten-e/ monitor/pub.htm, no. 50, date: February 15, 2006). Though both studies are not representative for the German population, they provide at present the best available data basis for deriving reference values for arsenic, cadmium, lead, and mercury in blood or urine of children.
General remarks The reference value is defined as the 95th percentile of the distribution of concentrations of a specific compound or element in a body fluid of a reference population (Ewers et al., 1999). Reference values for pollutants in urine are expressed as mg/l urine (and no longer as mg/g creatinine). In line with the WHO recommendations (WHO, 1996), the commission decided when deriving reference values to include only urine samples with creatinine levels in the range between 0.3 and 3.0 g/l. For human biomonitoring in environmental medicine it is recommended that in individual cases of values exceeding the reference value, a repeated sampling should be performed and care should be taken that the urine exhibits a normal dilution, i.e., a creatinine content between 0.5 and 2.5 g/l (Human Biomonitoring Commission, 2005b). When applying the reference values an analytical uncertainty of 720% should be considered.
Data basis The data basis is comprised of 2 studies. The survey performed in south-west Germany is a repeated crosssectional study started in 1992 (Landesgesundheitsamt Baden-Wu¨rttemberg, 2002, 2005). Each winter (October–March) school children (4th grade, age 9–11 years) from well-defined urban and rural areas are studied during this ‘‘Sentinel Health Departments of BadenWu¨rttemberg’’ project. Human biomonitoring comprises arsenic, some metals and persistent organic pollutants. Details on sampling of the study population,
questionnaire, sampling for analysis, analysis, statistical methods are given in a report (Landesgesundheitsamt Baden-Wu¨rttemberg, 2002). GerES are population-representative studies (Seifert et al., 2000). In the pilot study for GerES IV, the survey on children, children and adolescents aged 0–17 years were selected at random at four study areas (urban vs. rural and east vs. west Germany). The survey was conducted between March 2001 and March 2002 (Seifert et al., 2002, http://www.umweltbundesamt.de/survey-e/ pub/BriefDescription_January2005_2.pdf, date: February 15, 2006). The methods used (sampling of study population, questionnaire, sampling for analysis, analysis, statistical data treatment) are described in the final report ‘‘Pre-test for the Environmental Survey for Children and Adolescents’’ (Umweltbundesamt, 2004, http://www.umweltbundesamt.de/survey/pub/Pilotstudie_ 2001–02.htm, date: February 15, 2006). For an update of the reference values derived earlier for 6–12-year-old children, only the results for this age group are taken from the GerES IV pilot study. To analyze arsenic, cadmium and mercury in urine, spontaneous urine samples were taken in the ‘‘Sentinel Health Departments in Baden-Wu¨rttemberg’’ project, whereas morning urine samples were used in the GerES IV pilot study. The comparison of creatinine concentrations in spontaneous urine and morning urine did not show substantial differences. Therefore, it seemed to be acceptable to make use of the results of both methods to determine reference values.
Arsenic in urine Arsenic was determined with the hydride batch method. The results on arsenic levels in urine of both surveys are summarized in Table 1. Recent and frequent fish consumption led to higher arsenic values in urine (Human Biomonitoring Commission, 2003). As expected the arsenic concentrations in urine were mainly influenced by the recent fish consumption (see Table 1). Clear trends could be observed for the arsenic levels in urine of children over the last years in Germany. For the first time, a reference value for arsenic in urine of children is derived. The reference value of 15 mg/l is set for children aged 6–12 years who had no fish consumption during the preceding 48 h before sampling. For human biomonitoring of arsenic in environmental medicine it is recommended that any fish consumption during the last 48 h before sampling is avoided. Other potential sources than fish consumption causing higher levels of arsenic in urine could be local supply of drinking water contaminated with arsenic, mineral water, also that for medical treatment, arsenic-containing drugs or exposure to arsenic-contaminated dust or soil, e.g. from industrial waste.
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Table 1. Concentrations of arsenic, cadmium and mercury in urine (mg/l) as well as of cadmium, lead, and mercury in blood (mg/l) of children from the ‘‘Sentinel Health Departments of Baden-Wu¨rttemberg’’ project 2002/03 (BW-EHS) (Landesgesundheitsamt, 2005) and the pilot study for the German Environmental Survey on Children 2001/02 (GerES IV pilot study) (http:// www.umweltbundesamt.de/survey/pub/Bericht_Pretest-3.pdf, Schulz et al., 2002) and reference values for children aged 6-12 years (right colums; according to Human Biomonitoring Commission, 2005a) Substance/Groups
N
NoLOQ
P 50
P 95
Arsenic in urine (lg/l) All BW-EHS (age 9–11 years) All GerES IV pilot study (age 6–12 years)
508 252
0 5
4.6 4.8
19.4 13.9
No fish consumption during preceding 48 h BW-EHS GerES IV pilot study
428 197
0 5
4.4 4.5
13.4 11.4
Fish consumption during preceding 48 h BW-EHS Ger ES IV pilot study
62 46
0 0
7.8 7.0
39.6 34.3
Cadmium in urine (lg/l) Non-smokers GerES IV pilot study (6–12 years)
248
74
0.10
0.38
Mercury in urine (lg/l) All BW-EHS (age 9–11 years) All GerES IV pilot study (age 6–12 years)
510 252
330 46
o 0.2 0.2
1.2 0.852b
Without teeth with amalgam fillings BW-EHS GerES IV pilot study
406 216
264 41
o 0.2 0.2
0.55 0.6
With teeth with amalgam fillings BW-EHS GerES IV pilot study
66 33
0 4
0.4 0.4
3.7 2.6
Cadmium in blood (lg/l) Non-smokers BW-EHS (age 9–11 years) GerES IV pilot study (age 6–12 years)
430 231
43 128
0.25 o 0.12
0.49 0.32
0.46–0.51b 0.23–0.38c
Lead in blood (lg/l) All BW-EHS (age 9–11 years) All GerES IV pilot study (age 6-12 years)
430 234
42 2
20.7 24
37.9 52
37.2–41.5b 46–55b
Mercury in blood (lg/l) All GerES IV pilot study (age 6-12 years)
233
73
0.20
1.00
Consumption of fish p 3 times/month Consumption of fish43 times/month
166 67
58 15
0.20 0.30
0.80 1.56
CI 95 PP
Reference valuea
15.0 lg/l 13.2–16.5b 12.1–16.8b
0.5 lg/l 0.31–0.45c 0.36–0.52b
0.7 lg/l 0.40–0.49b 0.40–0.77c
0.5 g/l
50 lg/l
0.6–1.0c
1.0 lg/l
N ¼ number of samples; LOQ ¼ limit of quantification; valuesoLOQ were set to LOQ/2; P50, P 95 ¼ percentiles; CI 95 PP ¼ 95% confidence interval for P 95 of the population percentile. Urine samples with creatinine levelso0.3 or43.0 mg/l are excluded when deriving the reference values. a An analytical uncertainty of 720% has to be taken into account when using the reference values. b Parametric procedure. c Bootstrapping procedure.
Cadmium in blood and urine The results on cadmium levels in blood of both surveys are summarized in Table 1. Cadmium levels in urine were only available from the GerES IV pilot study (Table 1). The cadmium concentrations in blood and
urine of adults were mainly influenced by tobacco smoke exposure (Human Biomonitoring Commission, 1998), therefore the reference values for cadmium in blood and urine were set for non-smoking persons. In contrast to adults no influence of tobacco smoke exposure on cadmium in blood and urine of children was observed.
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Compared with the former GerES II (1990/92) a decline of cadmium levels in urine and blood of children could not be detected clearly. Thus the former reference values of 0.5 mg/l blood and 0.5 mg/l urine established by the commission in 1998 were maintained. Increased cadmium levels in urine and blood can be due to active tobacco smoking, uptake with food, or intake of cadmium-containing dust and soil from industrial waste (Human Biomonitoring Commission, 2005a).
Lead in blood The results on lead levels in blood of both surveys are summarized in Table 1. Compared to the results of former surveys there is a decrease of the mean blood lead concentration of children. Thus, the reference values for lead in blood of 60 mg/l (Human Biomonitoring Commission, 1996) established by the Commission in 1996 was lowered to 50 mg/l for children aged 6-12 years. Sources or pathways for elevated lead content in blood could be lead-contaminated drinking water (if water pipes in old building are still containing lead), frequent eating of acid food from dishes with leadcontaining glaze or hot drinks from ceramics, exposure to metallic lead (e.g. New Year’s Eve custom in Germany of telling fortunes by the shapes made by molten lead dropped into cold water), exposure to leadcontaining ammunition, and the uptake of dust or soil contaminated with lead, e.g. from industrial waste (Human Biomonitoring Commission, 2005a).
number of amalgam fillings. Compared to former studies mercury levels in urine had decreased. Thus the reference value of 1.4 mg/l established by the commission in 1999 was lowered to 0.7 mg/l for children aged 6–12 years without teeth with amalgam fillings. Sources for increased mercury levels in urine could be teeth with amalgam fillings, frequent consumption of fish and seafood (both crustaceans and molluscs), the uptake of mercury vapors in the home due to broken clinical thermometers containing liquid mercury, or mercurycontaining drugs and bleaching ointments (Human Biomonitoring Commission, 2005a).
Recommendations in cases of values exceeding the reference values A repeat measurement should be performed in cases of concentrations exceeding the reference value. If reliable (checked several times) measurements show a value above the reference value, they should induce an environmental medicine-based search for sources. Such search should be carried out in a proportionate way. It must be emphasized that reference values are statistically derived and do not represent toxicologically derived biological exposure limits. Thus, they cannot be used for health-related evaluation of human biomonitoring data. Nevertheless, the reference values permit to assess the exposure of individuals or population groups compared to the ubiquitous background exposure.
Mercury in blood and urine Mercury in blood reflects the internal exposure resulting from organic and inorganic mercury (Human Biomonitoring Commission, 1999). Mercury blood levels were only available from the GerES IV pilot study (Table 1). Compared to the levels observed in GerES II (1990/92) there was a marked decrease of mercury blood levels for children. Consequently, the currently existing reference value of 1.5 mg/l (Human Biomonitoring Commission, 1999) was lowered to 1.0 mg/l for children consuming fish up to three times per months. Elevated mercury levels of blood may be caused by frequent consumption of fish and seafood (both crustaceans and molluscs), by uptake of mercury vapors in the home due to broken clinical thermometers containing liquid mercury, or mercury-containing drugs (Human Biomonitoring Commission, 2005a). Mercury in urine reflects the exposure to inorganic mercury (Human Biomonitoring Commission, 1999). The results on mercury levels in urine of both surveys are summarized in Table 1. As expected the mercury concentrations in urine were mainly influenced by amalgam fillings (see Table 1). The levels increased with
Further perspectives As soon as data from the German Environmental Survey for Children (GerES IV) are available the Human Biomonitoring Commission will provide revised or new reference values for environmental pollutants for children.
Acknowledgements This report is based on a consensus paper of the Human Biomonitoring Commission. The authors thank the other members of the commission J. Angerer, W. Butte, R. Eckard, U. Ewers, B. Heinzow, U. Heudorf, A. Kappos, and H. Kruse for their co-operation.
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