Int Arch Occup Environ Hlth 35,245-256 (1975) © by Springer-Verlag 1975
Excretion Kinetics and Variability of Urinary Mercury inWorkers Exposed to Mercury Vapour* JERZY K PIOTROWSKI, BARBARA TROJANOWSKA and EWA M MOGILNICKA Department of Toxicological Chemistry, Institute of Environmental Research and Bioanalysis, Medical Academy of Lod 2, and Department of Biochemistry, Institute of Occupational Medicine in Lod 2 Received March 10, 1975 / Accepted May 7, 1975 Summary
Determinations of mercury in urine were made in samples collected (a) exposed prior to sampling urine has been
from workers that were:
sampled over 3 weeks'post-exposure period;
(b) currently exposed
pling on consecutive days of the working week;
sam-
(c) currently exposed -
urine sampled over 24 hrs, during working shift
(morning or afternoon)
and off work. Mercury excretion in group
(a) followed a two-term exponential equation
with rate constants of about 0 35 and O 01 day -1
Regardless of exposure
time pattern in all groups studied, a diurnal variation of urinary concentrations of mercury was observed with a maximum at night and morning hours, and minimal values in the afternoon
The great variability in Hg-
concentrations could have been related to the time of day at which the sampling took place, and partly to variation of urine excretion rate, the 2 factors being interrelated
Only a moderate variability in urinary con-
centrations of mercury was found when the sampling was instituted at a constant time of day, and when the results were standardized for specific gravity of urine. Key words: Urinary Mercury
Excretion Kinetics
Variability of.
Numerous authors (Teisinger et al , 1956 ; Turrian et al , 1956 ; Trojanowska et al , 1961) were directing attention to a great variability in levels of urinary mercury in persons exposed to vapour of this element in industry This variability has been considered as a serious obstacle for evaluation of exposure, or of body burden of mercury, as based on urinary assays Knowledge of 2 important aspects of metabolic *Investigations
supported in part by the Polish-American agreement
05-009-2 and 05-003-2 with NIOSH, USA.
245
kinetics of mercury in man has been deficient, namely: (a) the excretion kinetics of the element after prolonged exposure to mercury vapour, and (b) the relation of excretion rate to the time pattern (rhythm) of exposure The excretion kinetics of inorganic mercury in rats was reported by Cember (1962) and Trojanowska (1968) but available human data have been scanty (Miettinen, 1973) The diurnal variation of Hg-excretion by humans exposed in industry was studied by Molyneux (1966) on 2 subjects only. The data reported below refer to urinary levels of mercury in industrial workers in 3 different situations: (a) during 3 weeks after discontinuation of the exposure, (b) on consecutive exposure days of working week following 4 days off work, and (c) at various times of day, including working shift The results of this study permit specification of conditions for sampling and analysis of urine for mercury content that reduce considerably the variability of reported values.
METHODS The study was made on 3 series of individuals, according to the programme specified above Series I comprised 7 men exposed previously to mercury vapour in a chemical plant; the observation lasted 3 weeks of the workers' hospitalization. There were 14 female workers in series II, employed by a small factory manufactoring thermometers Eleven men were included in series III; they were working in a department of electrolytic chlorine production on 2 shifts (morning and afternoon). The details regarding the 3 series are presented in Table 1. Data referring to mercury air concentrations should be regarded as approximate only Moreover, it should be noted that whereas the female workers examined in series II were exposed continuously throughout the entire shift, the workers in series III were spending only part of the shift time in areas of mercury exposure. Mercury content in urine was determined by a method similar to that of Lindstedt (1970) using our own modification as described previously by Piotrowski et al , 1973 The urine (5 ml) was mineralized with K MnO 4 in acid medium and the excess of the oxydant was reduced with hydroxylamine hydrochloride. Thereafter the sample was reduced with stannous chloride in the aeration vessel, and the liberated elemental mercury removed by aeration (70 dm 3 /hr) Mercury concentration in the air stream was determined by means of a Mercury Vapour Concentration Meter (Hendrey Relays, Type R 3472) The same instrument was also used for screening the air concentrations of mercury (series III).
246
Table 1 (numbers outside of parentheses are the means; limit
Data on all series
values are in parenthesis) Series
I
II
III
Post exposure
Weekly rhythm
Daily rhythm
14
11
women
men
40 (25-53)
39
(34-50)
11
11
( 7-17)
period No
of subjects
7
Sex
men
Age
43
(27-62)
Duration of exposure
(years) 13 ( 5-23)
Working shifts
Subjects in sana-
( 1-22)
torium, 4 immedi-
One morning shift
Morning shifts 7 subjects;
ately following
Afternoon shifts -
last exposure, 3
4 subjects
following an intermission of 9-30 days Length of
20 days
observation
day)
(every
9-day perioda
Time of urine
Morning urine;
a) Morning urine
Every 2 hrs with
collection
afternoon urine
b) At end of the
a 6 hr break
only for last
6 days within a
shift
1 day
during the night
4 days Mercury concentration in air
3 0.019 mg/m
(O.01-0 04 )b
0.070 mg/m3 (0.030-0
13 0
)c
a Observations started after a 4-day pause from work. b Data supplied by the factory. c Present authors' measurements.
Evaluation of the data was based on a comparison of the means; dispersion was characterized by coefficients of variation and/or a range of the value The significance of differences was tested using the Student's t-test The kinetic equation was obtained graphically in a semi-logarithmic coordinate system.
247
RESULTS Kinetics of Mercury Excretion Concentrations of mercury in the urine of 7 individuals followed up over a 3-week post-exposure period are presented in Table 2 For kinetic analysis of each individual, the concentrations in morning samples were expressed in percentage of The subject E was excluded from the analythe initial value The sis because of an unusually high variability in the data remaining data were subdivided: grouped separately for 3 workers admitted to the sanatorium immediately after the normal work routine was discontinued (subgroup a), and assembled for 3 other subjects for whom observation started only after The 2 sets of data in several days off work (subgroup b) Fig 1a and b indicate that mercury concentrations were diminishing slowly with time. The following features of excretion kinetics were observed in the 2 subgroups: 1 The initial rate of decrease of the concentrations in subgroup a was faster than toward the end of the period of observation and 2 The rate in subgroup b seemed constant throughout the period of follow-up, and accordingly could have been characterized by a single rate conIf this constant was accepted as stant of about O 01/day characteristic for the second slow component of the excretion, the constant for the first component, subgroup a, would be much The graphic analysis of Fig la yielded higher: about O 35/day the probable equation for mercury excretion in the post-exposure period: -O.35t -O O 1 t + O 74 e = 0 26 e Ct/C (1) t o where C t and C denote concentrations normalized to specific gravity of urine (1 024) in the off-work period and immediately after cessation of long-term exposure, respectively (t = time in days). Eq.( 1) demonstrates that systemic turnover of mercury is very slow; furthermore, it implies also that interruption of the daily rhythm of exposure on weekends should not lead to a marked deviation from excretory "plateau" of the steady state This contention has been confirmed by the data obtained in series II of this investigation Fig 2 demonstrates that urinary concentrations of mercury observed on Saturday and Monday did not differ significantly: in the morning urine a slight decrease was observed and in the afternoon samples some increase took place, the latter, however, was not sigAn increasing trend at the nificant statistically (t = 1 431) 1 at
248
=
O 05,
ta
=
2 07.
Table 2 Range of urinary mercury concentrations in 7 subjects over 20 days of hospitalization. Morning urine: concentrations specific gravity 1.024 Subject
(g/dm
) corrected to
Urinary mercury concentrations
Variability coefficient
1st day
mean and range of
entire
last
values over 20 days
period
10 days
calculated for
A
20th day
265
116
173 (116
265)
23
19
361
146
230 (143
361)
27
14
C
149
80
113
( 80
150)
17
15
D
672
333
424
(322
672)
22
12
197
190
240
(112
395)
36
35
55
49
57 ( 38
78)
18
19
294
186
225 (148
294)
16
15
22%
18 %
(16-36)
(12-35)
a B a
E F
a
G Mean
a Workers directed to sanatorium after several days' pause in exposure.
Fig la and b Urinary mercury concentrations in the post-exposure period values: 1st day = 100
Relative
Semi-logar-
ithmic scale: morning urine, mean values from 3 subjects (a) In subjects hospitalized immediately following last exposure,
(b) in
subjects with several days' pause _
5
10
15
20
ds
§
fo
t5
20 doys
_ _
_ _
_ _
e
_h _U
O
-A
ovation
vation
249
pq/d"' o
Z
7 75
QJ c W 0 50
0-lb
1 13 Q Z3
I Mon
I Tue
I ed
I Thu
F Fri
I Sat
Sun
Moiln
Ie ue
Fig 2 Urinary mercury concentrations in morning and afternoon urine to specific gravity 1 024) in 14 persons (series II)
(corrected
Mean values and
standard error
beginning of the observation period with regard to both the morning and afternoon samples collected between Monday and Friday of the first week may be interpreted as being due to the 4-day no-work interval before follow-up began, this led to manifestation in the steady level of the contribution of the first "rapid" term in Eq (1) This assumption does not explain a rising tendency observed for the afternoon urine samples in the further period of Friday of the first week until Tuesday of the second week; this, however, was not statistically significant (t = 1 401). The slow turnover rate of mercury should preclude excretory manifestation of the rhythm: exposure interval off work within working day In fact, Fig 3 shows that existing diurnal variation in mercury concentrations in urine may not be consistently linked to daily hours of exposure in morning and afternoon shifts (Fig 3a and b, respectively) Regardless of the latter, the concentrations were reaching a maximum at night and the troughs were in the afternoon Existence of this exposure-independent diurnal rhythm was also confirmed in the 2 remaining series; in the subjects observed during post-exposure period (Fig 4) and in women followed-up daily during the exposure interval (Fig 2) In both cases the morning values were systematically higher than those seen in the afternoon. Variability in Urinary Concentrations of Mercury In series III a great variability in urinary concentrations of mercury was observed In order to analyze this variability quantitatively it was assumed that part of the variation might 250
pgglhr
cm3 /hr
b
a
200
25 I t,
150
foo,
u Z
c t C) '
t
100
t
ZI 50
O,
.c
50
t u
7 9 11 3 15 17 92 23 f 3
f 5 1 19 2 23
3 5 7 9
1 43
_ _ _ __ J
E xpowre
Exposure
hours
Fig 3a and b Changes in urinary concentrations of mercury in subjects exposed on the morning (a) and afternoon (b) shifts
,u9/d 3 =
500
morning afternoon
i~
ri 400 c)
300
200
c 100
A Fig
A
8
C
II II N
D E u bects
F
G
4
Comparison of urinary mercury concentrations ity 1 024)
(corrected to specific grav-
in the morning and afternoon urine of persons observed during
the post-exposure period
(last 4 days)
251
14 *a
00
__r
40
3o
_
O
_
20 20
It
t 4
2
I L 5
i ii i 10 20 30 40 50 60 70
l
80
i, 90
I
95
98 99
%
Cumulative frequency Fig 5 Cumulative frequency of distribution of urinary mercury concentrations in 5 persons (series III)
yg/hr
lg/dm 3
'4
3
Q O 75
0 't
U
5o
X
50 CU
4
25
1
,,
~ I
25
I
50
I
I
75
100
Urine excretion rate
125 m 3/hr
Fig 6 Indices of urinary mercury as dependent upon the urine excretion rate (5 subjects, series III)
be due to differences in individual exposure To eliminate the possible influence of this factor, 5 persons were selected for refined analysis, whose mean Hg-concentrations in urine varied within a narrow range of 88-94 g/dm 3 Fig 5 shows the cumulative frequency of distribution of Hg-concentrations in discrete urine samples in these subjects The parameters of variability for concentrations corrected for a specific gravity of
252
1.024 were: median 80 g/dm 3, standard deviations of -35 and +50 g/dm 3 (the confidence limits of 16 and 84 % of cummulative frequency, respectively) corresponding to coefficients of variation of -44 and +63% If the concentrations were not corrected the coefficients of variation amounted to -58 and +79% This great spread of the data mainly reflects diurnal variation, as may be seen in Fig 3. Preliminary calculations have shown that the variability of urinary mercury concentrations parallels the variability of urine excretion rate Fig 6 shows that urinary mercury concentrations are inversely correlated with urine excretion rate. This reduction in concentrations could have been only partly compensated for by normalizing the concentrations for the standard specific gravity (1 024) On the other hand, the mercury excretion rate (g/hr) was rising with increasing urine excretion rate. The variability of urine excretion rate was much less pronounced in series I and II, where samples were taken at constant times of the day Accordingly, the variability of urinary Hg-concentrations in various individuals was much lower: for all indices in series II (morning and afternoon concentrations normalized to standard specific gravity, afternoon Hg-excretion rate), mean coefficients of variations were ±26 to 28% with respective values for individual subjects in the range of ±14 to ±52 % In series I, in which the subjects were studied in the post-exposure period and living conditions and nutrition were much the same for all individuals, during the last 10 days of the follow-up the coefficients of variation were even more reduced: the mean was ±18 %, with values for all individuals except one below ±20%.
DISCUSSION AND CONCLUSIONS Limited kinetic data are available for mercury compounds in man Data obtained by Morsy & El Assaly (1970) for diphenyl mercury and by Johnson (1968) for neohydrine, indicated the half-time within the range of 10-30 days Miettinen (1973) estimated that the half-time of inorganic mercury compounds, administered orally to human subjects, amounted to 42 days. In the work reported here we have obtained approximate data on the kinetics of mercury excretion in urine following discontinuation of a long-term occupational exposure to mercury vapour lEq (1)l The exact numerical values of Eq (1) require further confirmation, especially with regard to the first rapid term for which the calculated coefficient is based merely on 3 subjects.
253
The biphasic curve of excretion resulting from the present observations has not been confirmed so far by other human data However, this type of excretion pattern seems consistent with the existing data on the excretion kinetics of mercury in animals (Cember, 1962 ; Trojanowska, 1968) It is worthwhile to note that the value of half-time reported by Miettinen (1973) is intermediate to those represented by the 2 terms of Eq (1) From this equation it follows that in persons exposed to mercury vapour for a prolonged time, the urinary level of the element should be quite constant, showing only slight dependence on moderate fluctuations of a systemic intake-rate of mercury as well as on temporary short breaks in exposure This results from the dominant contribution of the second term Eq (1)l to the body burden and excretion rate under steady state conditions The Hg pool with the fast turnover, accepted tentatively according to Eq (1) (half-time of about 2 days), contributed not more than 20 to 30 % to the excretion rate at steady state, and its disappearance within several days free of exposure may reduce only the excretion accordingly One may conclude therefore that in subjects exposed chronically to mercury, no distinct daily or weekly rhythm should become manifest that would follow rhythmic fluctuations of the exposure (see Piotrowski, 1971) This seems also consistent with the observations presented in this report regarding the daily and weekly rhythm of Hg-excretion. Regardless of the latter conclusion, the data presented in Figs 2-4 point to the existence of a diurnal rhythm with a maximum of concentrations at night and in the morning, and a minimum in the afternoon This rhythm, however, is not related to the daily rhythm of the exposure. The results presented in this paper shed some light on the "irregularity" of mercury excretion in urine The Hg-concentrations in discrete urine samples from the same individuals, collected at various times of the 24-hr interval (series III) showed a very great dispersion However when mercury determinations were made on various days, but at the same time of the day, the mean coefficients of variation dropped from about 42 to 26 % Standardization of living conditions during hospitalization resulted in a further reduction of the coefficient of variation, down to 18 % (Table 2) A value of the order of + 20% may therefore be obtained for urinary mercury if the most obvious factors contributing to the total variation are eliminated In this respect mercury does not seem to differ essentially from urinary lead (Elkins, 1961 ; Molyneux, 1964) which is often used as an index of the body burden. Thus, urinary mercury excretion in a given subject may be assessed precisely enough, provided the following conditions
254
are met: a) a constant time for urine sampling has to be established and a morning specimen is recommended; b) the concentrations should be corrected for specific gravity; c) the determinations should be limited to subjects exposed for a sufficiently long time to reach the steady state; d) only persons in generally good condition should be considered; particularly those showing signs of kidney damage should be eliminated from the analysis; e) collection of urine samples is recommended following not more than 1 to 2 days off work. How the levels of urinary mercury, obtained from an assay fulfilling the above conditions, relate to exposure or body burden is not yet clear and therefore warrents further study. Acknowledgements
The authors wish to express their gratitude to Dr
Jan
Bruzgielewicz, Factorial Health Service of the Chemical Works O§wiecim, and to Dr
Antoni Niepok 6j, Chief Medical Officer, Trade Union of Chem-
ists, for their kind assistance in organizing these studies. The skillful technical assistance of Miss Margorzata Piliszek, Mrs
Krystyna Wi Sniewska, and Mrs
Maria Walczak is gratefully acknow-
ledged.
REFERENCES Cember, H : The influence of the size of the dose on the distribution and elimination of inorganic mercury
Am Ind Hyg Ass J
23,
304-313 (1962)
Elkins, H B : Maximum permissible urinary concentrations: Their relationship to atmospheric maximum allowable concentrations Proceedings of the International Symposium on Maximum Allowable Concentrations of Toxic Substances in Industry
London: Butterworts 1961
Johnson, J E , Johnson, J A : A new value for the long component of the effective half-retention time of 203 Hg in the human 265-266 (1968) Lindstedt,
Health Physics 14,
G : A rapid method for the determination of mercury in urine.
Analyst 95, 264-271
(1970)
Miettinen, J K : Absorption and elimination of dietary mercury methylmercury in man T.W
(Hg2+) and
In: Mercury, mercurials and mercaptans, M W Miller,
Clarkson, eds , pp 23 3 -2 4 3
Springfield, Ill : Thomas 1973
Molyneux, M K B : Use of single urine samples for the assessment of lead absorption
Brit J industr Med
21, 203-209
(1964)
Molyneux, M K B : Observation of the excretion rate and concentration of mercury in urine Annals of Occup Hyg 9, 95-102 (1966) Morsy, S M , El Assaly, F M : Body elimination rates of 134 Cs, 203 Hg Health Physics 19, 769-773 (1970)
60
Co and
Piotrowski, J K : The application of metabolic and excretion kinetics to problems of industrial toxicology Printing Office 1971
Washington, D C : U S Government
255
Piotrowski, J K , Trojanowska, B , Mogilnicka, E : Determination of low mercury concentrations in urine with the use of mercury vapour concentration meter (in Polish) Med Pracy 24, 313-319 (1973) Teisinger, J , Skramovsky, St , Srbova, J : Chemical methods of investigations biological materials in industrial toxicology (in Czech ) Prague: SZN 1956 Trojanowska, B : The dynamics of distribution and excretion of mercury in rats (in Polish) D Pharm Thesis, Medical Academy, Poznah (1968) Trojanowska, B , Romejko, A , Piotrowski, J : Certain problems in the toxicology of mercury (in Polish) Med Pracy 12, 15-22 (1961) Turian, V H , Grandjean, E , Turian, V : Industriehygienische und mediSchweiz Med Wschr. zinische Untersuchungen in Quecksilberbetrieben 38, 1091-1096 (1956)
Doc
Dr
Jerzy K
Piotrowski
Department of Toxicological Chemistry Medical Academy Narutowicza 120 A 90-145 Z Sdz,
256
Poland
Excretion Kinetics and Variability of Urinary Mercury inWorkers Exposed to Mercury Vapour* JERZY K PIOTROWSKI, BARBARA TROJANOWSKA and EWA M MOGILNICKA Department of Toxicological Chemistry, Institute of Environmental Research and Bioanalysis, Medical Academy of Lod 2, and Department of Biochemistry, Institute of Occupational Medicine in Lod 2 Received March 10, 1975 / Accepted May 7, 1975 Summary
Determinations of mercury in urine were made in samples collected (a) exposed prior to sampling urine has been
from workers that were:
sampled over 3 weeks'post-exposure period;
(b) currently exposed
pling on consecutive days of the working week;
sam-
(c) currently exposed -
urine sampled over 24 hrs, during working shift
(morning or afternoon)
and off work. Mercury excretion in group
(a) followed a two-term exponential equation
with rate constants of about 0 35 and O 01 day -1
Regardless of exposure
time pattern in all groups studied, a diurnal variation of urinary concentrations of mercury was observed with a maximum at night and morning hours, and minimal values in the afternoon
The great variability in Hg-
concentrations could have been related to the time of day at which the sampling took place, and partly to variation of urine excretion rate, the 2 factors being interrelated
Only a moderate variability in urinary con-
centrations of mercury was found when the sampling was instituted at a constant time of day, and when the results were standardized for specific gravity of urine. Key words: Urinary Mercury
Excretion Kinetics
Variability of.
Numerous authors (Teisinger et al , 1956 ; Turrian et al , 1956 ; Trojanowska et al , 1961) were directing attention to a great variability in levels of urinary mercury in persons exposed to vapour of this element in industry This variability has been considered as a serious obstacle for evaluation of exposure, or of body burden of mercury, as based on urinary assays Knowledge of 2 important aspects of metabolic *Investigations
supported in part by the Polish-American agreement
05-009-2 and 05-003-2 with NIOSH, USA.
245
kinetics of mercury in man has been deficient, namely: (a) the excretion kinetics of the element after prolonged exposure to mercury vapour, and (b) the relation of excretion rate to the time pattern (rhythm) of exposure The excretion kinetics of inorganic mercury in rats was reported by Cember (1962) and Trojanowska (1968) but available human data have been scanty (Miettinen, 1973) The diurnal variation of Hg-excretion by humans exposed in industry was studied by Molyneux (1966) on 2 subjects only. The data reported below refer to urinary levels of mercury in industrial workers in 3 different situations: (a) during 3 weeks after discontinuation of the exposure, (b) on consecutive exposure days of working week following 4 days off work, and (c) at various times of day, including working shift The results of this study permit specification of conditions for sampling and analysis of urine for mercury content that reduce considerably the variability of reported values.
METHODS The study was made on 3 series of individuals, according to the programme specified above Series I comprised 7 men exposed previously to mercury vapour in a chemical plant; the observation lasted 3 weeks of the workers' hospitalization. There were 14 female workers in series II, employed by a small factory manufactoring thermometers Eleven men were included in series III; they were working in a department of electrolytic chlorine production on 2 shifts (morning and afternoon). The details regarding the 3 series are presented in Table 1. Data referring to mercury air concentrations should be regarded as approximate only Moreover, it should be noted that whereas the female workers examined in series II were exposed continuously throughout the entire shift, the workers in series III were spending only part of the shift time in areas of mercury exposure. Mercury content in urine was determined by a method similar to that of Lindstedt (1970) using our own modification as described previously by Piotrowski et al , 1973 The urine (5 ml) was mineralized with K MnO 4 in acid medium and the excess of the oxydant was reduced with hydroxylamine hydrochloride. Thereafter the sample was reduced with stannous chloride in the aeration vessel, and the liberated elemental mercury removed by aeration (70 dm 3 /hr) Mercury concentration in the air stream was determined by means of a Mercury Vapour Concentration Meter (Hendrey Relays, Type R 3472) The same instrument was also used for screening the air concentrations of mercury (series III).
246
Table 1 (numbers outside of parentheses are the means; limit
Data on all series
values are in parenthesis) Series
I
II
III
Post exposure
Weekly rhythm
Daily rhythm
14
11
women
men
40 (25-53)
39
(34-50)
11
11
( 7-17)
period No
of subjects
7
Sex
men
Age
43
(27-62)
Duration of exposure
(years) 13 ( 5-23)
Working shifts
Subjects in sana-
( 1-22)
torium, 4 immedi-
One morning shift
Morning shifts 7 subjects;
ately following
Afternoon shifts -
last exposure, 3
4 subjects
following an intermission of 9-30 days Length of
20 days
observation
day)
(every
9-day perioda
Time of urine
Morning urine;
a) Morning urine
Every 2 hrs with
collection
afternoon urine
b) At end of the
a 6 hr break
only for last
6 days within a
shift
1 day
during the night
4 days Mercury concentration in air
3 0.019 mg/m
(O.01-0 04 )b
0.070 mg/m3 (0.030-0
13 0
)c
a Observations started after a 4-day pause from work. b Data supplied by the factory. c Present authors' measurements.
Evaluation of the data was based on a comparison of the means; dispersion was characterized by coefficients of variation and/or a range of the value The significance of differences was tested using the Student's t-test The kinetic equation was obtained graphically in a semi-logarithmic coordinate system.
247
RESULTS Kinetics of Mercury Excretion Concentrations of mercury in the urine of 7 individuals followed up over a 3-week post-exposure period are presented in Table 2 For kinetic analysis of each individual, the concentrations in morning samples were expressed in percentage of The subject E was excluded from the analythe initial value The sis because of an unusually high variability in the data remaining data were subdivided: grouped separately for 3 workers admitted to the sanatorium immediately after the normal work routine was discontinued (subgroup a), and assembled for 3 other subjects for whom observation started only after The 2 sets of data in several days off work (subgroup b) Fig 1a and b indicate that mercury concentrations were diminishing slowly with time. The following features of excretion kinetics were observed in the 2 subgroups: 1 The initial rate of decrease of the concentrations in subgroup a was faster than toward the end of the period of observation and 2 The rate in subgroup b seemed constant throughout the period of follow-up, and accordingly could have been characterized by a single rate conIf this constant was accepted as stant of about O 01/day characteristic for the second slow component of the excretion, the constant for the first component, subgroup a, would be much The graphic analysis of Fig la yielded higher: about O 35/day the probable equation for mercury excretion in the post-exposure period: -O.35t -O O 1 t + O 74 e = 0 26 e Ct/C (1) t o where C t and C denote concentrations normalized to specific gravity of urine (1 024) in the off-work period and immediately after cessation of long-term exposure, respectively (t = time in days). Eq.( 1) demonstrates that systemic turnover of mercury is very slow; furthermore, it implies also that interruption of the daily rhythm of exposure on weekends should not lead to a marked deviation from excretory "plateau" of the steady state This contention has been confirmed by the data obtained in series II of this investigation Fig 2 demonstrates that urinary concentrations of mercury observed on Saturday and Monday did not differ significantly: in the morning urine a slight decrease was observed and in the afternoon samples some increase took place, the latter, however, was not sigAn increasing trend at the nificant statistically (t = 1 431) 1 at
248
=
O 05,
ta
=
2 07.
Table 2 Range of urinary mercury concentrations in 7 subjects over 20 days of hospitalization. Morning urine: concentrations specific gravity 1.024 Subject
(g/dm
) corrected to
Urinary mercury concentrations
Variability coefficient
1st day
mean and range of
entire
last
values over 20 days
period
10 days
calculated for
A
20th day
265
116
173 (116
265)
23
19
361
146
230 (143
361)
27
14
C
149
80
113
( 80
150)
17
15
D
672
333
424
(322
672)
22
12
197
190
240
(112
395)
36
35
55
49
57 ( 38
78)
18
19
294
186
225 (148
294)
16
15
22%
18 %
(16-36)
(12-35)
a B a
E F
a
G Mean
a Workers directed to sanatorium after several days' pause in exposure.
Fig la and b Urinary mercury concentrations in the post-exposure period values: 1st day = 100
Relative
Semi-logar-
ithmic scale: morning urine, mean values from 3 subjects (a) In subjects hospitalized immediately following last exposure,
(b) in
subjects with several days' pause _
5
10
15
20
ds
§
fo
t5
20 doys
_ _
_ _
_ _
e
_h _U
O
-A
ovation
vation
249
pq/d"' o
Z
7 75
QJ c W 0 50
0-lb
1 13 Q Z3
I Mon
I Tue
I ed
I Thu
F Fri
I Sat
Sun
Moiln
Ie ue
Fig 2 Urinary mercury concentrations in morning and afternoon urine to specific gravity 1 024) in 14 persons (series II)
(corrected
Mean values and
standard error
beginning of the observation period with regard to both the morning and afternoon samples collected between Monday and Friday of the first week may be interpreted as being due to the 4-day no-work interval before follow-up began, this led to manifestation in the steady level of the contribution of the first "rapid" term in Eq (1) This assumption does not explain a rising tendency observed for the afternoon urine samples in the further period of Friday of the first week until Tuesday of the second week; this, however, was not statistically significant (t = 1 401). The slow turnover rate of mercury should preclude excretory manifestation of the rhythm: exposure interval off work within working day In fact, Fig 3 shows that existing diurnal variation in mercury concentrations in urine may not be consistently linked to daily hours of exposure in morning and afternoon shifts (Fig 3a and b, respectively) Regardless of the latter, the concentrations were reaching a maximum at night and the troughs were in the afternoon Existence of this exposure-independent diurnal rhythm was also confirmed in the 2 remaining series; in the subjects observed during post-exposure period (Fig 4) and in women followed-up daily during the exposure interval (Fig 2) In both cases the morning values were systematically higher than those seen in the afternoon. Variability in Urinary Concentrations of Mercury In series III a great variability in urinary concentrations of mercury was observed In order to analyze this variability quantitatively it was assumed that part of the variation might 250
pgglhr
cm3 /hr
b
a
200
25 I t,
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7 9 11 3 15 17 92 23 f 3
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Exposure
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Fig 3a and b Changes in urinary concentrations of mercury in subjects exposed on the morning (a) and afternoon (b) shifts
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500
morning afternoon
i~
ri 400 c)
300
200
c 100
A Fig
A
8
C
II II N
D E u bects
F
G
4
Comparison of urinary mercury concentrations ity 1 024)
(corrected to specific grav-
in the morning and afternoon urine of persons observed during
the post-exposure period
(last 4 days)
251
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00
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It
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I L 5
i ii i 10 20 30 40 50 60 70
l
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95
98 99
%
Cumulative frequency Fig 5 Cumulative frequency of distribution of urinary mercury concentrations in 5 persons (series III)
yg/hr
lg/dm 3
'4
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0 't
U
5o
X
50 CU
4
25
1
,,
~ I
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I
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Urine excretion rate
125 m 3/hr
Fig 6 Indices of urinary mercury as dependent upon the urine excretion rate (5 subjects, series III)
be due to differences in individual exposure To eliminate the possible influence of this factor, 5 persons were selected for refined analysis, whose mean Hg-concentrations in urine varied within a narrow range of 88-94 g/dm 3 Fig 5 shows the cumulative frequency of distribution of Hg-concentrations in discrete urine samples in these subjects The parameters of variability for concentrations corrected for a specific gravity of
252
1.024 were: median 80 g/dm 3, standard deviations of -35 and +50 g/dm 3 (the confidence limits of 16 and 84 % of cummulative frequency, respectively) corresponding to coefficients of variation of -44 and +63% If the concentrations were not corrected the coefficients of variation amounted to -58 and +79% This great spread of the data mainly reflects diurnal variation, as may be seen in Fig 3. Preliminary calculations have shown that the variability of urinary mercury concentrations parallels the variability of urine excretion rate Fig 6 shows that urinary mercury concentrations are inversely correlated with urine excretion rate. This reduction in concentrations could have been only partly compensated for by normalizing the concentrations for the standard specific gravity (1 024) On the other hand, the mercury excretion rate (g/hr) was rising with increasing urine excretion rate. The variability of urine excretion rate was much less pronounced in series I and II, where samples were taken at constant times of the day Accordingly, the variability of urinary Hg-concentrations in various individuals was much lower: for all indices in series II (morning and afternoon concentrations normalized to standard specific gravity, afternoon Hg-excretion rate), mean coefficients of variations were ±26 to 28% with respective values for individual subjects in the range of ±14 to ±52 % In series I, in which the subjects were studied in the post-exposure period and living conditions and nutrition were much the same for all individuals, during the last 10 days of the follow-up the coefficients of variation were even more reduced: the mean was ±18 %, with values for all individuals except one below ±20%.
DISCUSSION AND CONCLUSIONS Limited kinetic data are available for mercury compounds in man Data obtained by Morsy & El Assaly (1970) for diphenyl mercury and by Johnson (1968) for neohydrine, indicated the half-time within the range of 10-30 days Miettinen (1973) estimated that the half-time of inorganic mercury compounds, administered orally to human subjects, amounted to 42 days. In the work reported here we have obtained approximate data on the kinetics of mercury excretion in urine following discontinuation of a long-term occupational exposure to mercury vapour lEq (1)l The exact numerical values of Eq (1) require further confirmation, especially with regard to the first rapid term for which the calculated coefficient is based merely on 3 subjects.
253
The biphasic curve of excretion resulting from the present observations has not been confirmed so far by other human data However, this type of excretion pattern seems consistent with the existing data on the excretion kinetics of mercury in animals (Cember, 1962 ; Trojanowska, 1968) It is worthwhile to note that the value of half-time reported by Miettinen (1973) is intermediate to those represented by the 2 terms of Eq (1) From this equation it follows that in persons exposed to mercury vapour for a prolonged time, the urinary level of the element should be quite constant, showing only slight dependence on moderate fluctuations of a systemic intake-rate of mercury as well as on temporary short breaks in exposure This results from the dominant contribution of the second term Eq (1)l to the body burden and excretion rate under steady state conditions The Hg pool with the fast turnover, accepted tentatively according to Eq (1) (half-time of about 2 days), contributed not more than 20 to 30 % to the excretion rate at steady state, and its disappearance within several days free of exposure may reduce only the excretion accordingly One may conclude therefore that in subjects exposed chronically to mercury, no distinct daily or weekly rhythm should become manifest that would follow rhythmic fluctuations of the exposure (see Piotrowski, 1971) This seems also consistent with the observations presented in this report regarding the daily and weekly rhythm of Hg-excretion. Regardless of the latter conclusion, the data presented in Figs 2-4 point to the existence of a diurnal rhythm with a maximum of concentrations at night and in the morning, and a minimum in the afternoon This rhythm, however, is not related to the daily rhythm of the exposure. The results presented in this paper shed some light on the "irregularity" of mercury excretion in urine The Hg-concentrations in discrete urine samples from the same individuals, collected at various times of the 24-hr interval (series III) showed a very great dispersion However when mercury determinations were made on various days, but at the same time of the day, the mean coefficients of variation dropped from about 42 to 26 % Standardization of living conditions during hospitalization resulted in a further reduction of the coefficient of variation, down to 18 % (Table 2) A value of the order of + 20% may therefore be obtained for urinary mercury if the most obvious factors contributing to the total variation are eliminated In this respect mercury does not seem to differ essentially from urinary lead (Elkins, 1961 ; Molyneux, 1964) which is often used as an index of the body burden. Thus, urinary mercury excretion in a given subject may be assessed precisely enough, provided the following conditions
254
are met: a) a constant time for urine sampling has to be established and a morning specimen is recommended; b) the concentrations should be corrected for specific gravity; c) the determinations should be limited to subjects exposed for a sufficiently long time to reach the steady state; d) only persons in generally good condition should be considered; particularly those showing signs of kidney damage should be eliminated from the analysis; e) collection of urine samples is recommended following not more than 1 to 2 days off work. How the levels of urinary mercury, obtained from an assay fulfilling the above conditions, relate to exposure or body burden is not yet clear and therefore warrents further study. Acknowledgements
The authors wish to express their gratitude to Dr
Jan
Bruzgielewicz, Factorial Health Service of the Chemical Works O§wiecim, and to Dr
Antoni Niepok 6j, Chief Medical Officer, Trade Union of Chem-
ists, for their kind assistance in organizing these studies. The skillful technical assistance of Miss Margorzata Piliszek, Mrs
Krystyna Wi Sniewska, and Mrs
Maria Walczak is gratefully acknow-
ledged.
REFERENCES Cember, H : The influence of the size of the dose on the distribution and elimination of inorganic mercury
Am Ind Hyg Ass J
23,
304-313 (1962)
Elkins, H B : Maximum permissible urinary concentrations: Their relationship to atmospheric maximum allowable concentrations Proceedings of the International Symposium on Maximum Allowable Concentrations of Toxic Substances in Industry
London: Butterworts 1961
Johnson, J E , Johnson, J A : A new value for the long component of the effective half-retention time of 203 Hg in the human 265-266 (1968) Lindstedt,
Health Physics 14,
G : A rapid method for the determination of mercury in urine.
Analyst 95, 264-271
(1970)
Miettinen, J K : Absorption and elimination of dietary mercury methylmercury in man T.W
(Hg2+) and
In: Mercury, mercurials and mercaptans, M W Miller,
Clarkson, eds , pp 23 3 -2 4 3
Springfield, Ill : Thomas 1973
Molyneux, M K B : Use of single urine samples for the assessment of lead absorption
Brit J industr Med
21, 203-209
(1964)
Molyneux, M K B : Observation of the excretion rate and concentration of mercury in urine Annals of Occup Hyg 9, 95-102 (1966) Morsy, S M , El Assaly, F M : Body elimination rates of 134 Cs, 203 Hg Health Physics 19, 769-773 (1970)
60
Co and
Piotrowski, J K : The application of metabolic and excretion kinetics to problems of industrial toxicology Printing Office 1971
Washington, D C : U S Government
255
Piotrowski, J K , Trojanowska, B , Mogilnicka, E : Determination of low mercury concentrations in urine with the use of mercury vapour concentration meter (in Polish) Med Pracy 24, 313-319 (1973) Teisinger, J , Skramovsky, St , Srbova, J : Chemical methods of investigations biological materials in industrial toxicology (in Czech ) Prague: SZN 1956 Trojanowska, B : The dynamics of distribution and excretion of mercury in rats (in Polish) D Pharm Thesis, Medical Academy, Poznah (1968) Trojanowska, B , Romejko, A , Piotrowski, J : Certain problems in the toxicology of mercury (in Polish) Med Pracy 12, 15-22 (1961) Turian, V H , Grandjean, E , Turian, V : Industriehygienische und mediSchweiz Med Wschr. zinische Untersuchungen in Quecksilberbetrieben 38, 1091-1096 (1956)
Doc
Dr
Jerzy K
Piotrowski
Department of Toxicological Chemistry Medical Academy Narutowicza 120 A 90-145 Z Sdz,
256
Poland
