Int Arch Occup Environ Health (1992) 64:49-57

Intemat-onal Arches

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Olpatioonaland

Environmental Health © Springer-Verlag 1992

Assessment of thyroid, testes, kidney and autonomic nervous system function in lead-exposed workers Jean-Philippe Gennart, Alfred Bernard, and Robert Lauwerys Industrial Toxicology and Occupational Medicine Unit, Catholic University of Louvain, Clos Chapelle-aux-Champs 30 54, B-1200 Brussels, Belgium Received November 20, 1991 / Accepted February 27, 1992

Summary The objective of the study was to assess whether moderate occupational exposure to lead may be associated with early changes in potential target organs (thyroid, testes, kidney, autonomic nervous system) Workers exposed to lead in a lead acid battery factory (n = 98; mean blood lead 51 gg/dl, range 40-75 gg/dl) and 85 control workers were examined None of the indicators of kidney function (in urine: retinol-binding protein, 2microglobulin, albumin, N-acetyl-p-D-glucosaminidase; in serum: creatinine, P2 -microglobulin), endocrine function (follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, thyroxine, triiodothyronine) and autonomic nervous system (R-R interval variations on the electrocardiogram) were correlated with lead exposure (blood lead or duration of exposure) or showed significantly different mean values between the exposed group and controls These results and an assessment of the published data suggest that compliance with the Directive of the Council of the European Communities on lead exposure (health surveillance in workers whose lead in blood exceeds 40 lg/dl and removal from exposure when blood lead exceeds 70-80 gg/dl) would prevent the occurrence of significant biological changes in the majority of lead-exposed workers. Key words: Lead Autonomic nervous system Hypothalamo-hypophyseal system Kidney function tests Thyroid hormones

Introduction According to a Directive of the Council of the European Communities ( 82/605/EEC), workers whose lead in blood exceeds 40 Vg/dl must be subjected to a health surveillance programme, and removal from exposure must take place when the blood lead (Pb B) level exceeds 70 or 80 gg/dl depending on the concentration of 6-aminolevulinic Offprint requests to: R Lauwerys

acid in urine (ALAU) or zinc protoporphyrin (ZPP) or ALA dehydratase in blood It is generally accepted that in adult male workers, PbB values ranging from 40 to 70 pg/dl may still be associated with various biological changes related to the heme biosynthesis pathway and with neuropsychological changes (mainly vague subjective complaints, alteration of some psychomotor performances and reduction of conduction velocity in peripheral nerves; for a review, see l 12, 61 l). Although disturbances in other organs or functions (thyroid, testes, kidney, autonomic nervous system) can occur after long-term exposure to lead, it is still debatable whether such changes can already be detected at PbB levels considered acceptable under the EEC directive on lead The present study was undertaken mainly to assess whether moderate exposure to lead may be associated with early biological changes in these potential target organs. Materials and methods The total study population involved 221 workers occupied in several factories located in the same district of the country Lead-exposed workers were employed in a lead acid battery factory The controls were recruited from the finishing department of the same factory, the maintenance department, the warehouse of a hospital and a chemical factory The final selection of the study population was based on the results of the biological analyses at the time of the survey and on information gathered by a questionnaire Eventually, 98 subjects considered as moderately exposed to lead (PbB between 40 and 80 jg/dl) and 85 subjects considered as non-occupationally exposed to lead (control group) were retained on the basis of the following criteria (a) Control and lead-exposed workers were neither currently nor previously exposed to mercury, cadmium or solvents, and at the time of the survey, their level of cadmium in urine was less than 2 gg/g creatinine (b) The medical history of the workers did not reveal neurologic or neuropsychiatric affections, renal diseases of known causes or current medications which might influence the results of the tests (-blockers, thyroid hormones, antidepressive agents) (c) The exposed workers were uninterruptedly exposed to lead for at least 1 year prior to the survey, and as already indicated above, their PbB should be above 40 Itg/dl at the time of the examination (d) The controls

50 were considered never to have been occupationally exposed to lead by the plant physician, and their PbB at the time of the survey was less than 40 lg/dl. A questionnaire collecting information about occupational and medical histories, smoking habits and alcohol consumption was given to each subject. A venous blood and a spot urine sample were collected in metal-free plastic tubes and containers during the examination A sample of urine was immediately transferred to a tube containing 0.5 ml phosphate buffer (1 M, p H 7 6) for 2-microglobulin determination All samples were kept at 4°C Within 10 h, a haematological analysis was performed on a Technicon H 1 system Serum and urine were divided in several aliquots and stored at -18 °C until analysis. Lead analyses in blood and urine and cadmium in urine were performed by electrothermal atomic absorption spectrometry with stabilised temperature platform furnace techniques coupled with a Zeeman effect background correction system (Perkin Elmer, Zeeman 3030) Measurement of the ZPP concentration in erythrocytes was carried out with a haematofluorimeter (Aviv Associates, Lakewood, N J ) and of ALAU by an automated colorimetric method l28l The renal function was evaluated by the determination in serum of 2 -microglobulin and creatinine l19 l and in urine of creatinine l21 l, retinol-binding protein, albumin, 32 -microglobulin and N-acetyl D-glucosaminidase (NAG) Serum or urinary proteins were measured by a latex immunoassay l5l and NAG by the fluorimetric assay of Tucker et al l 52l The creatinine clearance was predicted form serum creatinine, age and body weight using the formula proposed by Cockroft and Gault l8 l Radioimmunoassays were used for the determination of serum triiodothyronine, thyroxine, triiodothyronine resin uptake (Bioteckx, Friendswood, Tenn ), thyroid-stimulating hormone (Diagnostic Systems Laboratories, Webster, Tenn ), follicle-stimulating hormone and luteinizing hormone (Cambridge Medical Diagnostic, Billerica, Mass ) The free thyroxine index was calculated by multiplying the thyroxine result by the triiodothyronine resin uptake value The critical flicker fusion was determined using an instrument (model 12020, Lafayette Instruments, Lafayette) with two lamps flickering coincidently. The cardiac parasympathetic function was assessed by measuring the interval variation between the consecutive R waves on the electrocardiogram recording (speed 25 mm/min) The subject was in the supine position, and after his heart rate had become stabilized, the electrocardiogram was recorded for 1 min and, thereafter, during 10 consecutive deep breaths at a frequency of 6/min. The R-R interval was measured with a master gauge The following parameters were calculated: under normal (R-) and deep breathing (D-): (1) mean square successive differences of the R-R interval (R-MSSD, D-MSSD) and (2) coefficient of variation of the R-R interval (R-CV, D-CV) The ratio of the shortest to

longest R-R interval under deep breathing was also calculated (DS/L).

Results The population characteristics are summarized in Table 1 On the basis of the EEC criteria, the lead workers may be considered as moderately exposed to lead: 83% of them had a Pb B below 60 gg/dl, and none had a value exceeding 75 gg/dl No statistically significant difference in age, weight, height, smoking ( 53% smokers in controls, 49 % in exposed workers) and drinking habits and urinary cadmium level was observed between control and exposed workers No relationship between urinary cadmium and blood lead was found in the control or exposed population. In the total population, PbB was well correlated with log ZPP (r = 0 87, P = 0 0001) or log ALAU (r = O 64, P = 0 0001) The regression equations are: Log ZPP = 0.06 + (0 019 x PbB) and log ALAU = 0 37 + (0 008 x PbB). The average erythrocyte counts did not differ significantly between the two populations (Table 2) However, 4 exposed workers against none of the controls had less than 13 g haemoglobin/dl, considered as the limit value for defining anaemia l4l Furthermore, within the entire study group a significant negative correlation was found between blood lead and haemoglobin (regression equation: haemoglobin = 14 2-( 0 011 x Pb B), r= -0 22, p = 0 003) or haematocrit (haematocrit = 45 2 -( 0 035 x PbB), r = 0 24, P < 0 01). Among the various indicators of kidney function, only serum creatinine and the predicted creatinine clearance were significantly correlated with age in the control population (r = 0 24, P = 0 02 and r = 0 47, P < 0 01, re-

spectively), and these markers were thus age-adjusted before statistical analysis No effect of lead could be evidenced on the renal parameters, whether the comparison was made on the basis of mean values (Table 3) or on the basis of prevalences of abnormal results (i e exceeding the 95 % percentile value in the control group). No significant relation with PbB, ZPP, ALAU or length

Table 1 Characteristics of the study population Control workers (n = 85) Mean Age (years)

Duration of exposure (years) Lead in blood (pg/dl) Lead in urine (g/g creatinine) Zinc protoporphyrin (g/g Hb) 6-Aminolevulinic acid in urine (gg/g creatinine) Cadmium in urine (g/g creatinine) a Geometric mean b Geometric standard deviation

38 8

20 9 9 75 a 2 84 a 3 48 0 36a

Standard deviation 87

11 2 1 1

Exposed workers (n = 98) Range

Mean

Standard deviation

Range

24

37 7

83

22

10 6 51 0 57 8a 10 2 a 6 00

81 80 1 95 b 1 82 b 1 69

1 28 40 0 75 4 29-399 31 37 2 60 35

-55

1 73b 86b 33

4 4 -39 0 1 45-77 7 1 0 -19 0 1 60 6 30

2 13 b

0 04 1 96

0 36a

2 00 b

0 05

55

4 0 4 2 6

1 35

51 Table 2 Haematologic data

Haemoglobin (g/dl) Red blood cells (106/%m 3 ) Haematocrit

Control workers

Exposed workers

Mean

Standard Range deviation

Mean

Standard deviation

Range

14 9

0 77

14 7

0 99

12 4 -17 4

4 85

0 33

44 4

27

13 4 -16 8 3 99 5 58 38 2 -54 1

4 90

0 36

43 3

23

3 84 5 62 37 2 -49 4

(%) Table 3 Renal parameters Control workers Geometric mean Urine 2 -Microglobulin (g/g creatinine) Retinol-binding protein (pig/g creatinine) Albumin (mg/g creatinine) N-Acetyl-P, D-glucosaminidase (UI/g creatinine)

40 5 48 3

Serum Creatinine (mg/dl)a 32 -Microglobulin (mg/l) Predicted creatinine clearancea a

Exposed workers

Geometric standard deviation

Range

Geometric mean

Geometric standard deviation

43 2 50 6

2 71 22

2 8 -1876 27 989 0 44 0 06

23 21

4 2 -374 3 3 -203 6

5 79 1 19

2 71 2 90

0 81-139 0 09 68 98

4 72 1 08

2 23 2 71

1 07 1 54 110

1 15 1 23 1 23

0 83 1 99 0 97 2 50 70 6 -248

1 07 1 43 107

1 16 1 18 1 22

Range

33 7 12 2

0 76 1 85 1 10 2 30 49 0 176

Values standardized to 38 years of age

Table 4 Endocrine parameters Control workers

Triiodothyronine (ng/dl) Thyroxine (g/dl) Free thyroxine index (lg/dl) Thyroid-stimulating hormone (mU/1) Follicle-stimulating hormone (IU/1) Luteinizing hormone (IU/1)

Exposed workers

Geometric mean

Geometric standard deviation

Range

Geometric mean

Geometric standard deviation

Range

125 7 2 0

5 32 86 50

1 14 1 23 1 23 2 56

88 2 -172 6 46 16 3 1 80 6 50 0 04 4 92

125 6 7 40 2 86 0 51

1 1 1 3

88 4 -340 8 38 11 7 1 79 4 70 0 04-130 1

4 97

2 13

17

72 1

4 15

2 02

16

7 74

1 62

3 36 39 4

7 59

1 60

3 16 65 3

of exposure was found The total population was subdivided according to the results of the PbB (quartile distribution, or: < 20 gg/d, 20 < 40 tg/dl, 40 < 60 gg/dl, > = 60 g/dl), length of exposure (< 5 y, 5 < 10 y, 1015 y, > = 15 y) or according to the quartile distribution of ALAU and ZPP An analysis of variance did not reveal any significant difference between the subgroups. No effect of lead could be shown on the endocrine parameters (Table 4) The mean values and prevalences of abnormal values were compared between controls and exposed subjects or according to the quartile distribution of the indicators of exposure (PbB, ALAU,

19 25 23 65

42 2

ZPP or duration of exposure) No statistically significant difference was found. As expected, we found a significant age-related decrease in the R-R interval variation parameters The correlation coefficients were consistently higher after log transformation of the variables Correlation coefficients ranged from -0 24 for R-MSSD to -0 40 for D-S/L. Therefore, the individual values were age-adjusted on the basis of the regression equations between age and log-transformed parameters of the R-R interval variation found in the control population After this age-adjustment, no significant difference could be observed be-

52 Table 5 Age-adjusted R-R interval variation parameters and critical flicker fusion Control workers Geometric mean R-R interval at rest Variance (%) Mean square successive difference (s 2) R-R interval during deep breathing Variance (%) Mean square successive differences (s 2 ) Mean ratio shortest to longest R-R (%) Critical flicker fusion (ms)

71 9 0 073 311 0 0 123

Exposed workers

Geometric standard deviation

Range

2 29

15 0

2 58 2 72 1 10

0 012

Geometric mean

611 7 1 105

14 8 -3256 0 097

0 151

63 1 0 065 347 5 0 121

Geometric standard deviation

Range

2 21

14 8

2 26 2 56 1 11

511 7

0 016 13 9

0 530

-1756

0 090

0 144

77 1

1 10

60 6

94 6

75 8

1 10

56 1

90 4

39 5

1 06

34 9

43 9

39 3

1 08

35

45 1

tween exposed probands and controls (Table 5) as well as between the different subgroups established according to the biological indicators of exposure (PbB, ALAU, ZPP) or length of exposure The mean criterial flicker fusion was not different between exposed and control subjects (Table 5) However, among the 17 workers with PbB above 60 Ig/dl, 4 ( 6 5%) had a value under the 5 % percentile of the control workers against 2 over 43 (3 2%) among these with a PbB under 20 gtg/dl (X2 P = 0 048). This difference is not age-related since the mean age was not significantly different between those with results above or under the 95 % percentile value of the control group ( 38 7 and 37 3 years, respectively) No significant relationship between the various parameters related to the R-R interval variation and the criterial flicker fusion was found. Discussion This study was designed to assess whether lead exposure in compliance with the EEC directive on lead would still be associated with early functional changes in the thyroid, kidney, testes and autonomic nervous system Great care was take to make a good match between workers occupationally and non-occupationally exposed to lead. Hence, from a total of 221 workers, only 163 met the criteria to be enrolled in the study Comparison of our results with those reported in the literature suggests that lead in blood below 70 gg/dl is unlikely to be associated with significant changes in the above cited target organs. Prolonged heavy exposure to lead may induce a progressive tubulointerstitial nephropathy which may result in renal failure and contracted kidney This nephropathy was described by several investigators in intoxicated workers l 56l, consumers of illicitly distilled alcohol l34l or after childhood poisoning l20 l During the past 20 years, a great number of epidemiologic studies on lead workers have been carried out in order to identify the early renal changes which might be predictive of clinical nephropathy Their main findings are summarized in Ta-

ble 6 Signs of reduced glomerular filtration were found by a few authors but usually among workers with Pb B > 60 pg/dl In the present study, we failed to show any change in serum creatinine or 32-microglobulin in the lead-exposed workers nor any relationship with the intensity or duration of exposure In studies on workers with similar PbB levels, other authors also failed to find a decreased glomerular filtration rate estimated on the basis of creatinine clearance l7, 36 l A few authors have reported signs of tubular dysfunction in lead-intoxicated workers l9, 24l However, in asymptomatic lead-exposed workers, an increased excretion of 0 2-microglobulin has not been found l36, 43l A correlation between urinary lead and NAG was found by Ong et al l37 l These authors, however, did not correct NAG activity for the urinary creatinine concentration This may explain the good correlation between lead in urine and NAG despite the absence of a significant correlation with PbB The possible influence of other nephrotoxic substances such as cadmium which is frequently associated with lead at many workplaces has not been taken into account by several authors who reported a change in some renal parameters such as retinol-binding protein or NAG in lead-exposed workers l33, 55l In the present study there was no difference in urinary cadmium between exposed and control workers nor any relationship between the various indicators of kidney function and urinary cadmium Therefore, our results support the biological threshold value of 60 gtg lead/dl blood for the prevention of renal effects l7, 14 l in adult male workers Whether this limit also applied to other groups of the general population remains to be established. It is known that lead may interfere with thyroid function Robins et al l40l found depressed thyroid indices in 7 among 12 foundry workers referred for clinical examination because of Pb B levels above 40 tg/dl and in 12 among 47 workers examined during a cross-sectional study (PbB ranging from 16 to 127 ltg/dl) The normal thyroid-stimulating hormone level in subjects with low thyroid indices suggested a central effect on the hypothalamopituitary axis The abnormal values were mainly

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Assessment of thyroid, testes, kidney and autonomic nervous system function in lead-exposed workers.

The objective of the study was to assess whether moderate occupational exposure to lead may be associated with early changes in potential target organ...
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