The Science of the Total Environment, 120 (1992) 117-125 Elsevier Science Publishers B.V., Amsterdam
117
The microdose problem and the most commonly used metals V. Foa a and A. Ferioli b'' ~Institute of Occupational Health, University of Bari, Bari, Italy bDepartment of Occupational Health, University of Brescia/Brescia Civic Hospital, Brescia, Italy ABSTRACT On the basis of recent research a relationship may exist between microexposure to metals and certain diseases (e.g. neurological and cardiovascular diseases) which occur in the later stages of life. This fact must be kept firmly in mind in view of the implications for the quality of health, considering the increase in average life expectancy. Moreover, it will be necessary to re-identify the critical organ for each metal, bearing in mind that the effects are altered in low level exposure conditions.
Key words: microdose; metals; cordiovascular disease; neurological diseases INTRODUCTION
Before addressing the topic of the possible effects of low-level exposure to metals, an attempt must be made to define what is meant by microdose, For this purpose, we shall propose a number of criteria in an attempt to 'numerically' define microexposure. According to their possible effects on health, metals can be divided into: essential metals (Table 1); metals not considered to be essential for the human body and thus the only metals for which the term 'toxic' seems to be appropriate. An element is essential when an insufficient intake can impair one or more functions and when a return to physiological levels, by means of a supplementary intake, eliminates or prevents the impairment. Thus, in the case of essential elements, both an increase or a decrease in the daily intake can cause adverse effects, whereas only an excessive intake of 'toxic' metals can cause adverse effects on health (Fig. 1). Furthermore, in contrast to non-essential metals, very few of the essential *Present address: International Centre for Pesticide Safety Health (ICPS), Local Unit 69, Busto Garolfo, Italy.
118
v. FOA AND A. FERIOLI
TABLE 1 Essential elements for the human body (see Ref. 5) Element
pH 7 form
Human amt.
Plasma conc.
Daily allowance
Na K Mg Ca Cr Mo Mn
Na ÷ K÷ Mg 2÷ Ca 2+ Cr(OH)~ MoO42Mn 2÷
100 g 140 g 19 g 1000 g 6 mg 9 mg 12 mg
141 mM 4 mM 0.9 mM 2 mM 0.5 #M 0.05 #M 0.2/~M
1-2 g 2-5 g 0.7 g 0.8 g 0.1 mg 0.3 mg 4 mg
Fe Fe Co Ni Cu Zn P S Se F CI I
FeO(OH)Q Fe2+ 3
20/zM
10-20 mg
0.1 #M 0.1 #M 18 #M 20 #M 2 mM 1 mM 2 #M 10 izM 103 mM 0.5 t~M
3 #g~ b 3 mg 15 mg 1g
4.2 g 1 mg 1 mg 72 mg 2.3 g 780 g 140 g 5 mg 2.6 g 95 g 30 mg
Co 2+
Ni 2+ CuOl Zn 2+ HPO 2SO24HSeO 3 FCII-
0.1 g 2 mg 2-4 g 0.15 mg
aVitamin B12. bEssentiality indicated in animals only.
~ /
OPTIMAL~"'~
~ EXGESS
MARGINAL
/ / DEFICIENT RESPONSE ................
ESSENTIAL ~",. \,\
.,.,C,c \ CONCENTRATION
'\\
POSSIBLEDEATH
\
Fig. 1. Biological response dependence on tissue concentration of an essential element (solid curve) and of a toxic substance (dashed curve). The relative position of the two curves on the concentration axis is arbitrary and one of convenience (see Ref. 5).
THE MICRODOSE PROBLEM AND THE MOST COMMONLY USED METALS
119
metals give rise to a pathological state as a result of accumulation. This is presumably due to the fact that the receptor sites can rarely reach saturation and thus an interaction/effect with other molecular 'targets'. In the case of non-essential metals, however, where only an excessive intake causes effects, a direct correlation has been demonstrated between increase in dose and biological effect. For the essential metals it is proposed to define, as exposure to microdoses, the range of concentrations between the mean requirement dose and the lowest dose producing a biological effect that can be ascribed to absorption of the metal. For the non-essential metals exposure to microdoses can be quantified at exposure levels which raise the internal dose indicator from a hypothetical 'zero' to the lowest dose producing a biological effect that can be ascribed to absorption of the metal. Clearly, this definition raises serious evaluation problems, especially in the case of non-essential metals where there are wide inter-individual variations in the requirement dose. BIOLOGICAL EFFECTS OF EXPOSURE TO MICRODOSES OF METALS
A large amount of evidence has been acquired over the last few years concerning the existence of significant biological effects in subjects with lowlevel exposure to occupational toxics [1]. Of the effects reported for the most commonly used metals, we shall examine, in particular, the effects on the cardiovascular and the central nervous systems.
Cardiovascular system As shown in Table 2 there is rather strong evidence for the role of lead as a risk factor in cardiovascular disease. In particular, a causal relationship was observed between lead exposure and blood pressure, even at low levels of exposure, i.e. with Pb blood levels (Pb-B) below 30/~g/100 ml (Fig. 2). Even if this relationship is weak, serious attention should be dedicated to this fact in view of the possible health implications for the general population. Pirkle et al. [2] analyzed the trend of Pb-B values in adult male white Americans during the period 1976-1980 and found a reduction of about 37% in the mean Pb-B value, which fell from 16.7/~g/100 ml in 1976 to 10.5/~g/100 ml in 1980. In the authors' view, this variation will, over the next 10 years, lead to a reduction of 4.7% in the frequency of cardiac infarction, of 6.7% in the frequency of cerebral-vascular stroke, and a reduction of 17.5% in hypertension (diastolic pressure >_90 m m Hg) (Table 3). The mean Pb-B values observed in subjects occupationally exposed at the
120
v. FOAANDA.FERIOLI
TABLE 2 Classification of possible risk factors for cardiovascular disease (CVD) in the work environment (see Ref. 6) Casual relation to CVD
Very definite Quite definite
Risk factor Nonchemical
Chemical
Physical inactivity at work Work strain (high demands and low influence), shift work, noisea
Carbon disulfide nitroglycerin/nitroglycol Lead~, passive smoking
Possible Somewhat possible Probably no relationship
Heat b, irradiation power frequency magnetic fields, low-frequency noise Microwaves, coldb
Cobalt, arsenic, combustion products Organophosphates dinitrotoluene, antimony, beryllium, carbon monoxideb Cadmium, organic solvents¢
alncreases the risk for CVD through increased blood pressure. bHigh-level exposure may be fatal, especially when combined with other risk factors. CHigh-level exposure may cause cardiac arrhythmia and sudden death.
workplaces where good industrial hygiene conditions exist are - 3 5 #g/100 ml (Fig. 3), which corresponds to the 98 percentile of the distribution of Pb-B values in the general population, as indicated in the European Community Directive on Lead (1982). However, these values are at least 3-times higher than the mean values observed in the American population in 1980. It is therefore conceivable that a large percentage of cardiovascular disease (cardiac infarction, stroke, hypertension) is due to lead exposure even in situations where there is good industrial hygiene practice. Central nervous system
The neurotoxic effects of abnormal absorption of metals commonly used in industry have been widely known for many years. In more recent years, with more sophisticated investigation techniques available, it has been possible to demonstrate effects on the central nervous system even at low-level exposure. For example, studies on neuro-endocrine function have revealed significant effects on neuro-hormone incretion in exposures to aluminium,
121
THE MICRODOSE PROBLEM AND THE MOST COMMONLY USED METALS
ADJUSTED DIASTOLIC 9o BLOOD PRESSURE (ram Hg)
.
J
e8 86 84 82 80 7~ 0
•
4
8
12
16
20
24
28
32
36
ADJUSTED BLOOD LEAD LEVELS 0Jg/dl)
ADJUSTED SYSTOLIC BLOOD PRESSURE
140
(ram Hg) 135 •
f
130.
125
120
115
0
~,
8
12
16
20
2"4
2~]
32
3(;
ADJUSTED BLOOD LEAD LEVELS (pg/dl)
Fig. 2. Adjustedblood pressure values for white males aged 40-59 years (see Ref. 2). manganese and lead below the present environmental and biological exposure limits [3]. The aim of this paper is to draw attention in particular to the recently reported hypothesis concerning the possible combined effects of exposure to neurotoxic substances and cerebral aging [4], according to which exposure to xenobiotics having toxic effects on specific regions of the central nervous system could be one of the causes of a number of neuro-degenerative diseases; the lesions could remain in a sub-clinical state for decades, but the subject would then be particularly susceptible to the consequences of neurone degeneration associated with aging (Fig. 4). This hypothesis is based on the association observed between a number of neurological diseases, and exposure to certain environmental toxics and, in certain diseases, on the long latency period between absorption of the substance and appearance of neurological symptoms (Table 4).
Fatal and non-fatal myocardial infarctions Fatal and non-fatal strokes
10 10
Follow-up period (years)
1 636 200 413 200
Before 37% decrease in blood lead
1 560 900 385 700
After 37% decrease in blood lead
Predicted number of events during follow-up period
77 300 27 500
Absolute difference in number of events
4.7 6.7
% Difference in number of events
Predicted change in number of serious outcomes as a result of the 37% decrease in blood lead levels in adult white males aged 40-49 years (see Ref. 2)
TABLE 3
to
123
THE MICRODOSE PROBLEM AND THE MOST COMMONLY USED METALS
50 mean (pg/lO0 ml)
PbB
45 40 35
............
~ ~ -:ii~ ....................
30
25
1979
20
' 1980
1981
19~2
' 1983
years
Fig. 3. Behaviour of blood lead levels of workers of 4 battery plants in the period 1979-1983. The solid curve represents the general behaviour (see Ref. 7).
600] •
o
I
I
•
I
I
"1
600-~ 400
"
.~ 200]
~
o-
C 0 "
Z
-
60o
¢e
i
i
]
i
I
|
'i"
;,.:".ii..,.......;.,
40200
I
0
20
40 60 80 Age (years)
I
100
Fig. 4. Age-related decline in number of neurons in human substantia nigra (top), medial basal forebrain (centre), and motor neurones of the lumbosacral spinal cord (bottom) (see Ref. 4).
124
v . F O A A N D A. F E R I O L I
TABLE 4 Associations observed between neurological diseases and exposure to environmental toxics Neurologic disease
Environmental factor
Parkinson Amyotrophic lateral sclerosis (ALS) + Parkinsonism (PD) + Dementia (ALS-PD Guam complex) Lathyrism (Spastic paraparesis)
Methylphenyltetrahydropyridine(MPTP) Guam life-style(Consumption of cycad seed containing B.M.A.A.)
Consumption of chickling pea (~-N-oxalylamino-L-alanine-BOAA)
A dose-reponse relationship can be expected for neurone damage due to exposure to environmental neurotoxics. In particular, the severity of the initial lesions could influence the length of the latency period and the pattern of sub-clinical deficiencies. Figure 5 shows the hypothetical behaviour over time of the effects of acute exposure on neurone count. We believe the above observations warrant investigations on the possibility of an interaction with the physiological mechanisms of brain aging and
NEURONAL POPULATION % 100-
80-
60-
40-
20-
0 25
I 50
I 75
a 100
I 125
I 150
^ ¢~- 1:7
Fig. 5. Theoreticalmodel of combined effectsof toxic exposure and age. The arrow indicates the effect of assumption of MPTP on the nigro-striatai neurones (from a suggestion by Prof. P. Spencer, 1989).
THE MICRODOSE PROBLEM AND THE MOST COMMONLY USED METALS
125
thus with the possible loss of neurones in occupationally exposed subjects also in the field of microdose exposure to metals. This is also in the light of the above mentioned neurotoxic effects observed in low-level exposure to some commonly used metals in industry. FINAL REMARKS Even though there are undoubtedly many weak points in the proposed definitions and hypotheses, nevertheless there is no doubt that the possibility of a relationship between low-level exposure to metals and certain diseases occurring only in the later stages of life must be kept firmly in mind in view of the implications for the quality o f health besides the social implications, considering the increase in average life expectancy and also the possible synergic or summational effects of exposure to both environmental and occupational risk factors. It will therefore be necessary to re-identify the critical organ for each metal, bearing in mind that the effects are altered in low-level exposure conditions and that the organs described in the established definitions may not be the first to reach the critical concentration. REFERENCES 1 V. Foa and A. Ferioli, Chemicals at low doses and disease. Med. Lav., 1 (1990) 11-21. 2 J.L. Pirkle, J. Schwartz, J.R. Landis et al., The relationship between blood lead levels and blood pressure and its cardiovascular risk implications. Am. J. Epidemiol., 121 (1985) 246-258. 3 A. Ferioli, P. Apostoli, L. Romeo, L. Alessio, Interferenzedei metalli sul sistema neuroendocrino: gli esempi del piombo, manganese ed alluminio in soggetti professionalmente esposti. Atti 53 Congresso Societa' Italiana di Medicina del Lavoro ed Igiene Industriale, Stresa 10-13 ottobre 1990, in press. 4 D.B. Calne, A. Eisen, E. McGeer and P. Spencer, Alzheimer'sdisease, Parkinson's disease and motorneurone disease: abiotropic interaction between ageing and environment. Lancet, ii (1986) 1067-1070. 5 R.B. Martin, Bioinorganic chemistry of toxicity, in H.G. Seiler, H. Sigel and A. Sigel (Eds.), Handbook on Toxicity of Inorganic Compounds, Dekker, New York and Basel, 1988, Ch. 2, pp. 9-37. 6 T.S. Kristensen, Cardiovascular diseases and the work environment. Scand. J. Work Environ. Health, 15 (1989) 245-264. 7 P. Apostoli, G. MaraneUi and E. Gaffuri, Evoluzione del rischio da piombo nell'industria degli accumulatori. Arch. Sci. Lav., 2 (1986) 1-8.
117
The microdose problem and the most commonly used metals V. Foa a and A. Ferioli b'' ~Institute of Occupational Health, University of Bari, Bari, Italy bDepartment of Occupational Health, University of Brescia/Brescia Civic Hospital, Brescia, Italy ABSTRACT On the basis of recent research a relationship may exist between microexposure to metals and certain diseases (e.g. neurological and cardiovascular diseases) which occur in the later stages of life. This fact must be kept firmly in mind in view of the implications for the quality of health, considering the increase in average life expectancy. Moreover, it will be necessary to re-identify the critical organ for each metal, bearing in mind that the effects are altered in low level exposure conditions.
Key words: microdose; metals; cordiovascular disease; neurological diseases INTRODUCTION
Before addressing the topic of the possible effects of low-level exposure to metals, an attempt must be made to define what is meant by microdose, For this purpose, we shall propose a number of criteria in an attempt to 'numerically' define microexposure. According to their possible effects on health, metals can be divided into: essential metals (Table 1); metals not considered to be essential for the human body and thus the only metals for which the term 'toxic' seems to be appropriate. An element is essential when an insufficient intake can impair one or more functions and when a return to physiological levels, by means of a supplementary intake, eliminates or prevents the impairment. Thus, in the case of essential elements, both an increase or a decrease in the daily intake can cause adverse effects, whereas only an excessive intake of 'toxic' metals can cause adverse effects on health (Fig. 1). Furthermore, in contrast to non-essential metals, very few of the essential *Present address: International Centre for Pesticide Safety Health (ICPS), Local Unit 69, Busto Garolfo, Italy.
118
v. FOA AND A. FERIOLI
TABLE 1 Essential elements for the human body (see Ref. 5) Element
pH 7 form
Human amt.
Plasma conc.
Daily allowance
Na K Mg Ca Cr Mo Mn
Na ÷ K÷ Mg 2÷ Ca 2+ Cr(OH)~ MoO42Mn 2÷
100 g 140 g 19 g 1000 g 6 mg 9 mg 12 mg
141 mM 4 mM 0.9 mM 2 mM 0.5 #M 0.05 #M 0.2/~M
1-2 g 2-5 g 0.7 g 0.8 g 0.1 mg 0.3 mg 4 mg
Fe Fe Co Ni Cu Zn P S Se F CI I
FeO(OH)Q Fe2+ 3
20/zM
10-20 mg
0.1 #M 0.1 #M 18 #M 20 #M 2 mM 1 mM 2 #M 10 izM 103 mM 0.5 t~M
3 #g~ b 3 mg 15 mg 1g
4.2 g 1 mg 1 mg 72 mg 2.3 g 780 g 140 g 5 mg 2.6 g 95 g 30 mg
Co 2+
Ni 2+ CuOl Zn 2+ HPO 2SO24HSeO 3 FCII-
0.1 g 2 mg 2-4 g 0.15 mg
aVitamin B12. bEssentiality indicated in animals only.
~ /
OPTIMAL~"'~
~ EXGESS
MARGINAL
/ / DEFICIENT RESPONSE ................
ESSENTIAL ~",. \,\
.,.,C,c \ CONCENTRATION
'\\
POSSIBLEDEATH
\
Fig. 1. Biological response dependence on tissue concentration of an essential element (solid curve) and of a toxic substance (dashed curve). The relative position of the two curves on the concentration axis is arbitrary and one of convenience (see Ref. 5).
THE MICRODOSE PROBLEM AND THE MOST COMMONLY USED METALS
119
metals give rise to a pathological state as a result of accumulation. This is presumably due to the fact that the receptor sites can rarely reach saturation and thus an interaction/effect with other molecular 'targets'. In the case of non-essential metals, however, where only an excessive intake causes effects, a direct correlation has been demonstrated between increase in dose and biological effect. For the essential metals it is proposed to define, as exposure to microdoses, the range of concentrations between the mean requirement dose and the lowest dose producing a biological effect that can be ascribed to absorption of the metal. For the non-essential metals exposure to microdoses can be quantified at exposure levels which raise the internal dose indicator from a hypothetical 'zero' to the lowest dose producing a biological effect that can be ascribed to absorption of the metal. Clearly, this definition raises serious evaluation problems, especially in the case of non-essential metals where there are wide inter-individual variations in the requirement dose. BIOLOGICAL EFFECTS OF EXPOSURE TO MICRODOSES OF METALS
A large amount of evidence has been acquired over the last few years concerning the existence of significant biological effects in subjects with lowlevel exposure to occupational toxics [1]. Of the effects reported for the most commonly used metals, we shall examine, in particular, the effects on the cardiovascular and the central nervous systems.
Cardiovascular system As shown in Table 2 there is rather strong evidence for the role of lead as a risk factor in cardiovascular disease. In particular, a causal relationship was observed between lead exposure and blood pressure, even at low levels of exposure, i.e. with Pb blood levels (Pb-B) below 30/~g/100 ml (Fig. 2). Even if this relationship is weak, serious attention should be dedicated to this fact in view of the possible health implications for the general population. Pirkle et al. [2] analyzed the trend of Pb-B values in adult male white Americans during the period 1976-1980 and found a reduction of about 37% in the mean Pb-B value, which fell from 16.7/~g/100 ml in 1976 to 10.5/~g/100 ml in 1980. In the authors' view, this variation will, over the next 10 years, lead to a reduction of 4.7% in the frequency of cardiac infarction, of 6.7% in the frequency of cerebral-vascular stroke, and a reduction of 17.5% in hypertension (diastolic pressure >_90 m m Hg) (Table 3). The mean Pb-B values observed in subjects occupationally exposed at the
120
v. FOAANDA.FERIOLI
TABLE 2 Classification of possible risk factors for cardiovascular disease (CVD) in the work environment (see Ref. 6) Casual relation to CVD
Very definite Quite definite
Risk factor Nonchemical
Chemical
Physical inactivity at work Work strain (high demands and low influence), shift work, noisea
Carbon disulfide nitroglycerin/nitroglycol Lead~, passive smoking
Possible Somewhat possible Probably no relationship
Heat b, irradiation power frequency magnetic fields, low-frequency noise Microwaves, coldb
Cobalt, arsenic, combustion products Organophosphates dinitrotoluene, antimony, beryllium, carbon monoxideb Cadmium, organic solvents¢
alncreases the risk for CVD through increased blood pressure. bHigh-level exposure may be fatal, especially when combined with other risk factors. CHigh-level exposure may cause cardiac arrhythmia and sudden death.
workplaces where good industrial hygiene conditions exist are - 3 5 #g/100 ml (Fig. 3), which corresponds to the 98 percentile of the distribution of Pb-B values in the general population, as indicated in the European Community Directive on Lead (1982). However, these values are at least 3-times higher than the mean values observed in the American population in 1980. It is therefore conceivable that a large percentage of cardiovascular disease (cardiac infarction, stroke, hypertension) is due to lead exposure even in situations where there is good industrial hygiene practice. Central nervous system
The neurotoxic effects of abnormal absorption of metals commonly used in industry have been widely known for many years. In more recent years, with more sophisticated investigation techniques available, it has been possible to demonstrate effects on the central nervous system even at low-level exposure. For example, studies on neuro-endocrine function have revealed significant effects on neuro-hormone incretion in exposures to aluminium,
121
THE MICRODOSE PROBLEM AND THE MOST COMMONLY USED METALS
ADJUSTED DIASTOLIC 9o BLOOD PRESSURE (ram Hg)
.
J
e8 86 84 82 80 7~ 0
•
4
8
12
16
20
24
28
32
36
ADJUSTED BLOOD LEAD LEVELS 0Jg/dl)
ADJUSTED SYSTOLIC BLOOD PRESSURE
140
(ram Hg) 135 •
f
130.
125
120
115
0
~,
8
12
16
20
2"4
2~]
32
3(;
ADJUSTED BLOOD LEAD LEVELS (pg/dl)
Fig. 2. Adjustedblood pressure values for white males aged 40-59 years (see Ref. 2). manganese and lead below the present environmental and biological exposure limits [3]. The aim of this paper is to draw attention in particular to the recently reported hypothesis concerning the possible combined effects of exposure to neurotoxic substances and cerebral aging [4], according to which exposure to xenobiotics having toxic effects on specific regions of the central nervous system could be one of the causes of a number of neuro-degenerative diseases; the lesions could remain in a sub-clinical state for decades, but the subject would then be particularly susceptible to the consequences of neurone degeneration associated with aging (Fig. 4). This hypothesis is based on the association observed between a number of neurological diseases, and exposure to certain environmental toxics and, in certain diseases, on the long latency period between absorption of the substance and appearance of neurological symptoms (Table 4).
Fatal and non-fatal myocardial infarctions Fatal and non-fatal strokes
10 10
Follow-up period (years)
1 636 200 413 200
Before 37% decrease in blood lead
1 560 900 385 700
After 37% decrease in blood lead
Predicted number of events during follow-up period
77 300 27 500
Absolute difference in number of events
4.7 6.7
% Difference in number of events
Predicted change in number of serious outcomes as a result of the 37% decrease in blood lead levels in adult white males aged 40-49 years (see Ref. 2)
TABLE 3
to
123
THE MICRODOSE PROBLEM AND THE MOST COMMONLY USED METALS
50 mean (pg/lO0 ml)
PbB
45 40 35
............
~ ~ -:ii~ ....................
30
25
1979
20
' 1980
1981
19~2
' 1983
years
Fig. 3. Behaviour of blood lead levels of workers of 4 battery plants in the period 1979-1983. The solid curve represents the general behaviour (see Ref. 7).
600] •
o
I
I
•
I
I
"1
600-~ 400
"
.~ 200]
~
o-
C 0 "
Z
-
60o
¢e
i
i
]
i
I
|
'i"
;,.:".ii..,.......;.,
40200
I
0
20
40 60 80 Age (years)
I
100
Fig. 4. Age-related decline in number of neurons in human substantia nigra (top), medial basal forebrain (centre), and motor neurones of the lumbosacral spinal cord (bottom) (see Ref. 4).
124
v . F O A A N D A. F E R I O L I
TABLE 4 Associations observed between neurological diseases and exposure to environmental toxics Neurologic disease
Environmental factor
Parkinson Amyotrophic lateral sclerosis (ALS) + Parkinsonism (PD) + Dementia (ALS-PD Guam complex) Lathyrism (Spastic paraparesis)
Methylphenyltetrahydropyridine(MPTP) Guam life-style(Consumption of cycad seed containing B.M.A.A.)
Consumption of chickling pea (~-N-oxalylamino-L-alanine-BOAA)
A dose-reponse relationship can be expected for neurone damage due to exposure to environmental neurotoxics. In particular, the severity of the initial lesions could influence the length of the latency period and the pattern of sub-clinical deficiencies. Figure 5 shows the hypothetical behaviour over time of the effects of acute exposure on neurone count. We believe the above observations warrant investigations on the possibility of an interaction with the physiological mechanisms of brain aging and
NEURONAL POPULATION % 100-
80-
60-
40-
20-
0 25
I 50
I 75
a 100
I 125
I 150
^ ¢~- 1:7
Fig. 5. Theoreticalmodel of combined effectsof toxic exposure and age. The arrow indicates the effect of assumption of MPTP on the nigro-striatai neurones (from a suggestion by Prof. P. Spencer, 1989).
THE MICRODOSE PROBLEM AND THE MOST COMMONLY USED METALS
125
thus with the possible loss of neurones in occupationally exposed subjects also in the field of microdose exposure to metals. This is also in the light of the above mentioned neurotoxic effects observed in low-level exposure to some commonly used metals in industry. FINAL REMARKS Even though there are undoubtedly many weak points in the proposed definitions and hypotheses, nevertheless there is no doubt that the possibility of a relationship between low-level exposure to metals and certain diseases occurring only in the later stages of life must be kept firmly in mind in view of the implications for the quality o f health besides the social implications, considering the increase in average life expectancy and also the possible synergic or summational effects of exposure to both environmental and occupational risk factors. It will therefore be necessary to re-identify the critical organ for each metal, bearing in mind that the effects are altered in low-level exposure conditions and that the organs described in the established definitions may not be the first to reach the critical concentration. REFERENCES 1 V. Foa and A. Ferioli, Chemicals at low doses and disease. Med. Lav., 1 (1990) 11-21. 2 J.L. Pirkle, J. Schwartz, J.R. Landis et al., The relationship between blood lead levels and blood pressure and its cardiovascular risk implications. Am. J. Epidemiol., 121 (1985) 246-258. 3 A. Ferioli, P. Apostoli, L. Romeo, L. Alessio, Interferenzedei metalli sul sistema neuroendocrino: gli esempi del piombo, manganese ed alluminio in soggetti professionalmente esposti. Atti 53 Congresso Societa' Italiana di Medicina del Lavoro ed Igiene Industriale, Stresa 10-13 ottobre 1990, in press. 4 D.B. Calne, A. Eisen, E. McGeer and P. Spencer, Alzheimer'sdisease, Parkinson's disease and motorneurone disease: abiotropic interaction between ageing and environment. Lancet, ii (1986) 1067-1070. 5 R.B. Martin, Bioinorganic chemistry of toxicity, in H.G. Seiler, H. Sigel and A. Sigel (Eds.), Handbook on Toxicity of Inorganic Compounds, Dekker, New York and Basel, 1988, Ch. 2, pp. 9-37. 6 T.S. Kristensen, Cardiovascular diseases and the work environment. Scand. J. Work Environ. Health, 15 (1989) 245-264. 7 P. Apostoli, G. MaraneUi and E. Gaffuri, Evoluzione del rischio da piombo nell'industria degli accumulatori. Arch. Sci. Lav., 2 (1986) 1-8.
