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Scientific comment on the German human biological monitoring values (HBM values) for mercury
International Journal of Hygiene and Environmental Health
Int. J. Hyg. Environ. Health 205, 509 ± 512 (2002) ¹ Urban & Fischer Verlag http: // www.urbanfischer.de/journals/intjhyg
Commentary Scientific comment on the German human biological monitoring values (HBM values) for mercury G. Drasch, S. Bˆse-O'Reilly, S. Maydl, G. Roider Institute of Forensic Medicine, Ludwig-Maximilians-University, Munich, Germany Received February 6, 2002 ¥ Revision received March 11, 2002 ¥ Accepted April 4, 2002 Key words: Human biological monitoring ± mercury
In 1999 HBM values for mercury (Hg) in blood and urine were established in Germany (Kommission Human-Biomonitoring 1999). The ™HBM I value∫ (blood 5 mg/l; urine 5 mg/g creatinine) can be considered as a kind of an alert value, whereas the ™HBM II value∫ (blood 15 mg/l; urine 20 mg/g creatinine) represents an action level (Ewers et al. 1999). In principle, the HBM I is comparable to the NOAEL (no observed adverse effect level) and HBM II to the LOAEL (lowest observed adverse effect level). No differences are made for inorganic and organic mercury burden, nor for age or gender. We had the opportunity to verify these HBM values on a highly Hg burdened population in a gold mining area on Mindanao (Philippines) (Drasch et al. 2001). A mixed burden by Hg vapor, inorganic Hg and Methyl-Hg can be assumed in this population (Bˆse-O'Reilly et al. 2002). Two hundred and sixty-one burdened persons and 61 from a control area on the Philippines were included in this study. Blood, urine and hair samples were taken from each participant and analyzed for mercury. Anamnestic data were asked and extensive medical investigations and some neuro-psychological tests were performed (for details see Drasch et al. 2001). For this special evaluation eight of the examined medical parameters, characteristic for Hg intoxication were
selected: bluish discoloration of the gingiva, ataxia of gait, heel-to-knee ataxia, heel-to-knee tremor, nose tremor, dysdiadochokinesis, labial reflex and proteinuria (Drasch 1994, Florentine and Sanfilippo 1991, Grandjean 1999, Mita et al. 2001, National Research Council 2000, Von Burg and Greenwood 1991, WHO 1990, 1991). The frequency of all these adverse effects was much higher in the burdened group than in the control group (Table 1). But there was no increase of the frequencies with the HBM categories in the burdened group, as could be expected (Table 1). Most surprising was that in the burdened group even below HMB I in many cases the frequencies of adverse effects were much higher than in the control group. This means that at least in this highly burdened population a classification according to the HBM categories gives no prediction on the occurrence of any of the investigated adverse effects. To avoid a bias by alcohol, all statistics were repeated with the sub-population of females and children (up to 14 years), as it was proven that they have no larger alcohol consumption. Again, in this sub-population the frequencies of the Hg-associated adverse effects were much higher in the burdened area than in the control area, but again these frequencies were not related to the HBM categories (Table 2).
Corresponding author: Prof. Dr. Gustav Drasch, Institut f¸r Rechtsmedizin, Ludwig-Maximilians-Universit‰t M¸nchen, Frauenlobstr. 7a, D-80337 M¸nchen, Germany. Phone: 49 89 5160 5132, Fax: 49 89 5160 5144, E-mail: [email protected]
1438-4639/02/205-509 $ 15.00/0
510
G. Drasch et al.
Table 1. Prevalence of adverse effects according to HBM classes for mercury in blood and urine (all investigated persons). Parameter
Control
Burdened group Hg-blood
number of subjects % bluish discoloration of gingiva % ataxia of gait % ataxia heel to knee % tremor heel to knee % nose tremor % dysdiadochokinesis % positive labial reflex % proteinuria
41 2.4 0 17.1 14.6 14.6 22.0 17.1 4.9
Hg-urine
all
< HBM I
HBM I ± II
> HBM II
< HBM I
HBM I ± II
> HBM II
261 29.5 17.6 58.2 68.6 26.1 46.7 37.1 16.1
60 25.0 11.7 56.7 63.3 26.7 45.0 43.3 11.7
144 30.6 20.8 59.0 68.8 25.7 47.2 41.7 16.7
57 31.6 15.8 57.9 73.7 26.3 47.4 33.3 19.3
169 29.6 17.8 58.0 70.4 30.2 48.5 45.6 17.2
58 29.3 19.0 60.3 62.1 19.0 39.7 32.8 8.6
34 29.4 14.7 55.9 70.6 17.6 50.0 26.5 23.5
Table 2. Prevalence of adverse effects according to HBM classes for mercury in blood and urine (only females and children). Parameter
Control
Burdened group Hg-blood
number of subjects % bluish discoloration of gingiva % ataxia of gait % ataxia heel to knee % tremor heel to knee % nose tremor % dysdiadochokinesis % positive labial reflex % proteinuria
20 0.0 0.0 10.0 10.0 15.0 20.0 10.0 5.0
Hg-urine
all
< HBM I
HBM I ± II
> HBM II
< HBM I
HBM I ± II
> HBM II
132 15.9 12.9 45.5 56.1 17.4 34.8 28.0 16.7
46 10.9 13.0 45.7 56.5 17.4 39.1 34.8 8.7
70 17.1 14.3 50.0 61.4 17.1 34.3 24.3 21.4
16 25.0 6.3 25.0 31.3 18.8 25.0 25.0 18.8
98 16.3 14.3 48.0 62.2 20.4 39.8 32.7 19.4
24 16.7 8.3 41.7 37.5 8.3 20.8 12.5 0.0
10 10.0 10.0 30.0 40.0 10.0 20.0 20.0 30.0
Searching for the reasons for this unexpected result, the arguments for the deduction of the HBM values for mercury are of interest: For mercury in blood the HBM categories were derived from two larger studies about the influence of organic mercury from fish consumption during pregnancy on the development of the children on the Faroe islands and the Seychelles. From these studies the HBM commission concluded that adverse effects in the children occurred, if the mercury concentrations in the mothers' hair exceeded 5 mg/kg. This value was taken as threshold value. Further, from some recent studies it was derived that the ratio of mercury between blood (mg/l) and hair (mg/kg) is 1 : 250 to 1 : 350. From this ratio a HBM II value of 15 mg/l for mercury in blood was calculated. The HBM commission had no additional toxicological data to establish the HBM I value for mercury in blood. Therefore this value was set arbitrarily to 5 mg/l (Kommission Human-Biomonitoring 1999). The HBM commission assumed negative influences of the mercury burden of mothers during
pregnancy on the development of their children to be the critical adverse effect (i.e. the adverse effect which occurs first at an increasing burden). Unfortunately, such subtle pre-natal influences (Davidson et al. 1998, Grandjean and Weihe 1993, Grandjean et al. 1997) could not be verified in our study, due to the extreme adverse situation in field. But at least no significant differences could be registered for obviously massive damages of the foetus, as reported e.g. as fetal-type Minamata disease (Itai and Fujino 2001) or from the Iraq (Jernelˆv 2001). From our data we could prove a mean proportion of mercury in blood (mg/l) and in hair (mg/kg) of approximately 1 : 300 (median in our study 1 : 320). But on an individual basis, this factor varied in our population from 1 : 22 to 1 : 31 592! Therefore, to our comprehension, on an individual basis a fixed conversion factor of 1 : 300 is not appropriate for a toxicological evaluation. For mercury in urine no definite threshold value could be derived by the HBM commission from a meta-analysis of data on the N-acetyl-D-glucosami-
HBM values for Hg
Fig. 1. Box-plot of the mercury concentration in blood in relation to ataxia of gait for all burdened cases (The two dotted lines represent the HBM I and HBM II values).
dase (NAG) activity in urine, a sensitive indicator for a beginning tubular damage of the kidney. Nevertheless, at mercury concentrations in urine > 35 mg/g creatinine an increase of the NAG activity could be observed. In addition the HBM commission reported of some studies with small case numbers (< 50), which investigated the influence of mercury vapor on the nervous system. In the range of 5 to 50 mg/g creatinine neurological changes could be shown for some persons in these studies. But the toxicological relevance was unclear to the HBM commission. Therefore the HBM values for mercury in urine were established more or less arbitrary to 20 mg/g creatinine (HBM II) and 5 mg/g creatinine (HBM I) (Kommission Human-Biomonitoring 1999). Our results are not in contradiction to the HBM commission, because the HBM values have been derived from other adverse effects of mercury than the parameters investigated by us. It seems that the effects taken by the HBM commission for the establishment of the HBM limits were not the most critical ones. The higher frequency of characteristic neurological effects, as found by us in the Hg burdened population, seems to correspond better to the above mentioned small studies on the effect of mercury in work places on the neurological system, such as tremor, color vision, computerized EEC (electroencephalogram), somato-sensitive evoked potentials and the application of different behavioral tests (Benton, Santa Ana, Wechsler), which were not considered by the HBM commission, because the case numbers were too low for a generalization.
511
From our results it can be concluded that at least in the case of a chronic mixed burden by different mercury species (vapor, inorganic, organic) the mercury concentrations in blood and/or urine alone are not appropriate at all for the establishment of a toxicologically defined threshold limit like the HBM value. In Figure 1 this is exemplified by a box-plot showing the Hg concentration in blood related to the parameter ™ataxia of gait∫ in the burdened group: Neither the two actual HBM values, as plotted in the graph, nor any other Hg-blood value could be taken as a toxicological defined limit in the definition of HBM I or HBM II. The Hg-blood values of the two groups (with and without ataxia) overlap completely. For all other parameters similar results were achieved, for Hg-blood as for Hg-urine. This is the case for the total burdened group as for the children/ female or male subgroups separately. Our case numbers (261 burdened, 41 controls) allow such a solid statement. It is questionable, whether Hg concentrations in blood and urine really ™mirror∫ the concentration of the target tissues (Drasch et al. 1997, Weiner and Nylander 1993). Therefore the establishment of HBM values for mercury in blood and/or urine seems to be very critically. A more complex ranking, which includes some medical parameters in addition to the blood and urine values seems to be more appropriate.
References Bˆse-O'Reilly, S., Drasch, G., Beinhoff, C., Maydl, S., Vosko, M.R., Roider, G.: The Mt. Diwata study on the Philippines 2000 ± treatment of mercury intoxicated inhabitants of a gold mining area with DMPS (2,3-Dimercapto-1-propane-sulfonic acid, Dimaval). Sci. Tot. Environm., accepted for publication, 2002. Davidson, P. W., Myers, G. J., Cox, C., Axtell, C., Shamlaye, C., Sloane-Reeves, J., Cernichiari, E., Needham, L., Choi, A., Wang, Y., Berlin M, Clarkson, T. W.: Effects of prenatal and postnatal merthylmercury exposure from fish consumption on neurodevelopment. J. Am. Med. Assoc. 280, 701 ± 707 (1998). Drasch, G,: Mercury. In: Handbook on Metals in Clinical and Analytical Chemistry (H. Seiler, A. Sigel, H. Sigel, eds.). Marcel Dekker, New York 1994. Drasch, G., Wanghofer, E., Roider, G.: Are blood, urine, hair, and muscle valid bio-monitoring parameters for the internal burden of men with the heavy metals mercury, lead and cadmium? Trace Elem. Electrolytes 14, 116 ± 123 (1997). Drasch, G., Bˆse-O'Reilly, S., Beinhoff, C., Roider, G., Maydl, S.: The Mt. Diwata study on the Philippines 1999 ± assessing mercury intoxication of the population by small scale gold mining. Sci. Tot. Environm. 267, 151 ± 168 (2001).
512
G. Drasch et al.
Ewers, U., Krause, C., Schulz, C., Wilhelm, M.: Reference values and human biological monitoring values for environmental toxins. Int. Arch. Occup. Environ. Health 72, 255 ± 260 (1999). Florentine, M. J., Sanfilippo D. J.: Elemental mercury poisoning. Clin. Pharm. 10, 213 ± 221 (1991). Grandjean, P., Weihe, P.: Neurobehavioral effects of intrauterine mercury exposure: Potential sources of bias. Environ. Res. 61, 176 ± 183 (1993). Grandjean, P., Weihe, P., White, R. F., Debes, F., Araki, S., Yokoyama, K., Murata, K., Sorensen, N., Dahl, R., Jorgensen, P. J.: Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol. Teratol. 19, 417 ± 428 (1997). Grandjean, P.: Methylmercury. Neurotoxicity in Amazonian Children Downstream from Gold Mining. Environ. Health Perspect. 107, 587 ± 591 (1999). Itai, Y., Fujino, T.: A epidemiological study on the transition of the incidence of abnormal pregnancy in the area heavily contaminated with methyl mercury. Proceedings of the 6th Int Conference Mercury as a Global Pollutant, Minamata, Japan, 2001; pp. 226 ± 227. Jernelˆv, A.: Observations and lessons from the Iraq 1971 ± 72 concerning the toxicology of methylmercury. Proceedings of the 6th Int Conference Mercury as a Global Pollutant, Minamata, Japan, 2001; p. 241.
Kommission ™Human-Biomonitoring∫ des Umweltbundesamtes: Stoffmonographie Quecksilber ± Referenzund Human-Biomonitoring-Werte (HBM). Bundesgesundhbl. 42, 522 ± 532 (1999). Mita, S., Arima, T, Kimura, E., Hara, A., Hirano, T., Uyama, E., Sato, H., Uchino, M.: Neurological Features in Chronic Minamata Disease. Proceedings of the 6th Int Conference Mercury as a Global Pollutant, Minamata, Japan, 2001; p. 225. National Research Council (ed.): Toxicological Effects of Methylmercury. National Academic Press, Washington 2000. Von Burg, R., Greenwood, M. R.: Mercury. In: Metals and Their Compounds in the Environment (E. Merian, ed.), pp. 1043 ± 1088. VCH-Verlag, Weinheim, 1991. Weiner, J. A., Nylander, M.: The relationship between mercury concentration in human organs and different predictor variables. Sci. Tot. Environ. 138, 101 ± 115 (1993). WHO (World Health Organization) (ed.): Environmental Health Criteria 101: Methylmercury. Geneva 1990. WHO (World Health Organization) (ed.): Environmental Health Criteria 118: Inorganic Mercury. Geneva 1991.
Int. J. Hyg. Environ. Health 205, 509 ± 512 (2002) ¹ Urban & Fischer Verlag http: // www.urbanfischer.de/journals/intjhyg
Commentary Scientific comment on the German human biological monitoring values (HBM values) for mercury G. Drasch, S. Bˆse-O'Reilly, S. Maydl, G. Roider Institute of Forensic Medicine, Ludwig-Maximilians-University, Munich, Germany Received February 6, 2002 ¥ Revision received March 11, 2002 ¥ Accepted April 4, 2002 Key words: Human biological monitoring ± mercury
In 1999 HBM values for mercury (Hg) in blood and urine were established in Germany (Kommission Human-Biomonitoring 1999). The ™HBM I value∫ (blood 5 mg/l; urine 5 mg/g creatinine) can be considered as a kind of an alert value, whereas the ™HBM II value∫ (blood 15 mg/l; urine 20 mg/g creatinine) represents an action level (Ewers et al. 1999). In principle, the HBM I is comparable to the NOAEL (no observed adverse effect level) and HBM II to the LOAEL (lowest observed adverse effect level). No differences are made for inorganic and organic mercury burden, nor for age or gender. We had the opportunity to verify these HBM values on a highly Hg burdened population in a gold mining area on Mindanao (Philippines) (Drasch et al. 2001). A mixed burden by Hg vapor, inorganic Hg and Methyl-Hg can be assumed in this population (Bˆse-O'Reilly et al. 2002). Two hundred and sixty-one burdened persons and 61 from a control area on the Philippines were included in this study. Blood, urine and hair samples were taken from each participant and analyzed for mercury. Anamnestic data were asked and extensive medical investigations and some neuro-psychological tests were performed (for details see Drasch et al. 2001). For this special evaluation eight of the examined medical parameters, characteristic for Hg intoxication were
selected: bluish discoloration of the gingiva, ataxia of gait, heel-to-knee ataxia, heel-to-knee tremor, nose tremor, dysdiadochokinesis, labial reflex and proteinuria (Drasch 1994, Florentine and Sanfilippo 1991, Grandjean 1999, Mita et al. 2001, National Research Council 2000, Von Burg and Greenwood 1991, WHO 1990, 1991). The frequency of all these adverse effects was much higher in the burdened group than in the control group (Table 1). But there was no increase of the frequencies with the HBM categories in the burdened group, as could be expected (Table 1). Most surprising was that in the burdened group even below HMB I in many cases the frequencies of adverse effects were much higher than in the control group. This means that at least in this highly burdened population a classification according to the HBM categories gives no prediction on the occurrence of any of the investigated adverse effects. To avoid a bias by alcohol, all statistics were repeated with the sub-population of females and children (up to 14 years), as it was proven that they have no larger alcohol consumption. Again, in this sub-population the frequencies of the Hg-associated adverse effects were much higher in the burdened area than in the control area, but again these frequencies were not related to the HBM categories (Table 2).
Corresponding author: Prof. Dr. Gustav Drasch, Institut f¸r Rechtsmedizin, Ludwig-Maximilians-Universit‰t M¸nchen, Frauenlobstr. 7a, D-80337 M¸nchen, Germany. Phone: 49 89 5160 5132, Fax: 49 89 5160 5144, E-mail: [email protected]
1438-4639/02/205-509 $ 15.00/0
510
G. Drasch et al.
Table 1. Prevalence of adverse effects according to HBM classes for mercury in blood and urine (all investigated persons). Parameter
Control
Burdened group Hg-blood
number of subjects % bluish discoloration of gingiva % ataxia of gait % ataxia heel to knee % tremor heel to knee % nose tremor % dysdiadochokinesis % positive labial reflex % proteinuria
41 2.4 0 17.1 14.6 14.6 22.0 17.1 4.9
Hg-urine
all
< HBM I
HBM I ± II
> HBM II
< HBM I
HBM I ± II
> HBM II
261 29.5 17.6 58.2 68.6 26.1 46.7 37.1 16.1
60 25.0 11.7 56.7 63.3 26.7 45.0 43.3 11.7
144 30.6 20.8 59.0 68.8 25.7 47.2 41.7 16.7
57 31.6 15.8 57.9 73.7 26.3 47.4 33.3 19.3
169 29.6 17.8 58.0 70.4 30.2 48.5 45.6 17.2
58 29.3 19.0 60.3 62.1 19.0 39.7 32.8 8.6
34 29.4 14.7 55.9 70.6 17.6 50.0 26.5 23.5
Table 2. Prevalence of adverse effects according to HBM classes for mercury in blood and urine (only females and children). Parameter
Control
Burdened group Hg-blood
number of subjects % bluish discoloration of gingiva % ataxia of gait % ataxia heel to knee % tremor heel to knee % nose tremor % dysdiadochokinesis % positive labial reflex % proteinuria
20 0.0 0.0 10.0 10.0 15.0 20.0 10.0 5.0
Hg-urine
all
< HBM I
HBM I ± II
> HBM II
< HBM I
HBM I ± II
> HBM II
132 15.9 12.9 45.5 56.1 17.4 34.8 28.0 16.7
46 10.9 13.0 45.7 56.5 17.4 39.1 34.8 8.7
70 17.1 14.3 50.0 61.4 17.1 34.3 24.3 21.4
16 25.0 6.3 25.0 31.3 18.8 25.0 25.0 18.8
98 16.3 14.3 48.0 62.2 20.4 39.8 32.7 19.4
24 16.7 8.3 41.7 37.5 8.3 20.8 12.5 0.0
10 10.0 10.0 30.0 40.0 10.0 20.0 20.0 30.0
Searching for the reasons for this unexpected result, the arguments for the deduction of the HBM values for mercury are of interest: For mercury in blood the HBM categories were derived from two larger studies about the influence of organic mercury from fish consumption during pregnancy on the development of the children on the Faroe islands and the Seychelles. From these studies the HBM commission concluded that adverse effects in the children occurred, if the mercury concentrations in the mothers' hair exceeded 5 mg/kg. This value was taken as threshold value. Further, from some recent studies it was derived that the ratio of mercury between blood (mg/l) and hair (mg/kg) is 1 : 250 to 1 : 350. From this ratio a HBM II value of 15 mg/l for mercury in blood was calculated. The HBM commission had no additional toxicological data to establish the HBM I value for mercury in blood. Therefore this value was set arbitrarily to 5 mg/l (Kommission Human-Biomonitoring 1999). The HBM commission assumed negative influences of the mercury burden of mothers during
pregnancy on the development of their children to be the critical adverse effect (i.e. the adverse effect which occurs first at an increasing burden). Unfortunately, such subtle pre-natal influences (Davidson et al. 1998, Grandjean and Weihe 1993, Grandjean et al. 1997) could not be verified in our study, due to the extreme adverse situation in field. But at least no significant differences could be registered for obviously massive damages of the foetus, as reported e.g. as fetal-type Minamata disease (Itai and Fujino 2001) or from the Iraq (Jernelˆv 2001). From our data we could prove a mean proportion of mercury in blood (mg/l) and in hair (mg/kg) of approximately 1 : 300 (median in our study 1 : 320). But on an individual basis, this factor varied in our population from 1 : 22 to 1 : 31 592! Therefore, to our comprehension, on an individual basis a fixed conversion factor of 1 : 300 is not appropriate for a toxicological evaluation. For mercury in urine no definite threshold value could be derived by the HBM commission from a meta-analysis of data on the N-acetyl-D-glucosami-
HBM values for Hg
Fig. 1. Box-plot of the mercury concentration in blood in relation to ataxia of gait for all burdened cases (The two dotted lines represent the HBM I and HBM II values).
dase (NAG) activity in urine, a sensitive indicator for a beginning tubular damage of the kidney. Nevertheless, at mercury concentrations in urine > 35 mg/g creatinine an increase of the NAG activity could be observed. In addition the HBM commission reported of some studies with small case numbers (< 50), which investigated the influence of mercury vapor on the nervous system. In the range of 5 to 50 mg/g creatinine neurological changes could be shown for some persons in these studies. But the toxicological relevance was unclear to the HBM commission. Therefore the HBM values for mercury in urine were established more or less arbitrary to 20 mg/g creatinine (HBM II) and 5 mg/g creatinine (HBM I) (Kommission Human-Biomonitoring 1999). Our results are not in contradiction to the HBM commission, because the HBM values have been derived from other adverse effects of mercury than the parameters investigated by us. It seems that the effects taken by the HBM commission for the establishment of the HBM limits were not the most critical ones. The higher frequency of characteristic neurological effects, as found by us in the Hg burdened population, seems to correspond better to the above mentioned small studies on the effect of mercury in work places on the neurological system, such as tremor, color vision, computerized EEC (electroencephalogram), somato-sensitive evoked potentials and the application of different behavioral tests (Benton, Santa Ana, Wechsler), which were not considered by the HBM commission, because the case numbers were too low for a generalization.
511
From our results it can be concluded that at least in the case of a chronic mixed burden by different mercury species (vapor, inorganic, organic) the mercury concentrations in blood and/or urine alone are not appropriate at all for the establishment of a toxicologically defined threshold limit like the HBM value. In Figure 1 this is exemplified by a box-plot showing the Hg concentration in blood related to the parameter ™ataxia of gait∫ in the burdened group: Neither the two actual HBM values, as plotted in the graph, nor any other Hg-blood value could be taken as a toxicological defined limit in the definition of HBM I or HBM II. The Hg-blood values of the two groups (with and without ataxia) overlap completely. For all other parameters similar results were achieved, for Hg-blood as for Hg-urine. This is the case for the total burdened group as for the children/ female or male subgroups separately. Our case numbers (261 burdened, 41 controls) allow such a solid statement. It is questionable, whether Hg concentrations in blood and urine really ™mirror∫ the concentration of the target tissues (Drasch et al. 1997, Weiner and Nylander 1993). Therefore the establishment of HBM values for mercury in blood and/or urine seems to be very critically. A more complex ranking, which includes some medical parameters in addition to the blood and urine values seems to be more appropriate.
References Bˆse-O'Reilly, S., Drasch, G., Beinhoff, C., Maydl, S., Vosko, M.R., Roider, G.: The Mt. Diwata study on the Philippines 2000 ± treatment of mercury intoxicated inhabitants of a gold mining area with DMPS (2,3-Dimercapto-1-propane-sulfonic acid, Dimaval). Sci. Tot. Environm., accepted for publication, 2002. Davidson, P. W., Myers, G. J., Cox, C., Axtell, C., Shamlaye, C., Sloane-Reeves, J., Cernichiari, E., Needham, L., Choi, A., Wang, Y., Berlin M, Clarkson, T. W.: Effects of prenatal and postnatal merthylmercury exposure from fish consumption on neurodevelopment. J. Am. Med. Assoc. 280, 701 ± 707 (1998). Drasch, G,: Mercury. In: Handbook on Metals in Clinical and Analytical Chemistry (H. Seiler, A. Sigel, H. Sigel, eds.). Marcel Dekker, New York 1994. Drasch, G., Wanghofer, E., Roider, G.: Are blood, urine, hair, and muscle valid bio-monitoring parameters for the internal burden of men with the heavy metals mercury, lead and cadmium? Trace Elem. Electrolytes 14, 116 ± 123 (1997). Drasch, G., Bˆse-O'Reilly, S., Beinhoff, C., Roider, G., Maydl, S.: The Mt. Diwata study on the Philippines 1999 ± assessing mercury intoxication of the population by small scale gold mining. Sci. Tot. Environm. 267, 151 ± 168 (2001).
512
G. Drasch et al.
Ewers, U., Krause, C., Schulz, C., Wilhelm, M.: Reference values and human biological monitoring values for environmental toxins. Int. Arch. Occup. Environ. Health 72, 255 ± 260 (1999). Florentine, M. J., Sanfilippo D. J.: Elemental mercury poisoning. Clin. Pharm. 10, 213 ± 221 (1991). Grandjean, P., Weihe, P.: Neurobehavioral effects of intrauterine mercury exposure: Potential sources of bias. Environ. Res. 61, 176 ± 183 (1993). Grandjean, P., Weihe, P., White, R. F., Debes, F., Araki, S., Yokoyama, K., Murata, K., Sorensen, N., Dahl, R., Jorgensen, P. J.: Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol. Teratol. 19, 417 ± 428 (1997). Grandjean, P.: Methylmercury. Neurotoxicity in Amazonian Children Downstream from Gold Mining. Environ. Health Perspect. 107, 587 ± 591 (1999). Itai, Y., Fujino, T.: A epidemiological study on the transition of the incidence of abnormal pregnancy in the area heavily contaminated with methyl mercury. Proceedings of the 6th Int Conference Mercury as a Global Pollutant, Minamata, Japan, 2001; pp. 226 ± 227. Jernelˆv, A.: Observations and lessons from the Iraq 1971 ± 72 concerning the toxicology of methylmercury. Proceedings of the 6th Int Conference Mercury as a Global Pollutant, Minamata, Japan, 2001; p. 241.
Kommission ™Human-Biomonitoring∫ des Umweltbundesamtes: Stoffmonographie Quecksilber ± Referenzund Human-Biomonitoring-Werte (HBM). Bundesgesundhbl. 42, 522 ± 532 (1999). Mita, S., Arima, T, Kimura, E., Hara, A., Hirano, T., Uyama, E., Sato, H., Uchino, M.: Neurological Features in Chronic Minamata Disease. Proceedings of the 6th Int Conference Mercury as a Global Pollutant, Minamata, Japan, 2001; p. 225. National Research Council (ed.): Toxicological Effects of Methylmercury. National Academic Press, Washington 2000. Von Burg, R., Greenwood, M. R.: Mercury. In: Metals and Their Compounds in the Environment (E. Merian, ed.), pp. 1043 ± 1088. VCH-Verlag, Weinheim, 1991. Weiner, J. A., Nylander, M.: The relationship between mercury concentration in human organs and different predictor variables. Sci. Tot. Environ. 138, 101 ± 115 (1993). WHO (World Health Organization) (ed.): Environmental Health Criteria 101: Methylmercury. Geneva 1990. WHO (World Health Organization) (ed.): Environmental Health Criteria 118: Inorganic Mercury. Geneva 1991.