Occupational Exposure To Lead, Kidney Function Tests, And Blood Pressure
Mar 18, 2022
Contact: Audrey Hu audrey.hu@wecistanche.com
Antonio Cardozo dos Santos, et al
In the present study, we examined sensitive biochemical markers of kidney function and damage in 166 workers exposed to lead and in 60 control workers. The objective was to investigate the chronic renal toxicity of lead and its possible correlation with arterial pressure.
Diastolic arterial pressure was higher in the exposed group (p < 0.05), but the two groups did not differ in systolic pressure. The median activity of urinary N-acetyl-0-D-glucosaminidase was higher in the exposed group (p < 0.001). and correlated with blood lead levels (p < 0.001) and duration of exposure (p < 0.001), but not with arterial pressure. The other indicators studied, y-glutamyl-transpeptidase and alanine-aminopeptidase activity, urine albumin, and total urine protein were not higher than in the control group and were not correlated with blood lead, duration of exposure, or arterial pressure.
Keywords: biochemical markers, arterial pressure, kidney function, lead exposure
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INTRODUCTION
Toxicologic and epidemiologic studies have associated occupational and environmental exposure to lead with hypertension and nephropathy [ Batuman et al., 1983; Tyroler, 1988]. However, it is not clear whether the renal dysfunction attributed to lead is the consequence of a direct effect of the metal on the kidneys or a secondary result of the hypertensive effect of lead, or even of a combination of the two effects [Wedeen, 1988; Osterloh et al., 1989].
Some studies have demonstrated a positive association between lead in blood and hypertension, although without a change in functional renal capacity at relatively low levels of exposure [de Kort et al., 1987; Wedeen, 19881. However, these studies were based on tests considered to be of low sensitivity for the early detection of renal damage induced by lead [Lauwerys and Bernard, 1089; Omae et al., 1990]. Recently, despite the doubts about the real clinical significance of these alterations [WHO, 199 I], the determination of urinary enzyme activities has proved to be useful for the evaluation of the early effects of nephrotoxins [Meyer et al., 1984; Lauwerys and Bernard, 1987].
In the present study, we set out to evaluate the correlation between lead in blood, enzymatic, and blood pressure in an attempt to establish a more consistent association between lead nephrotoxicity and hypertension in individuals with a normal renal function who had been occupationally exposed to lead.
MATERIAL AND METHODS
Methodology
The cross-sectional type of epidemiologic study was used. In this type of study, 'past or future events are not taken into consideration, but only supposed cause respective effect at a given moment or within a given period of time are considered. Thus, an attempt is made to compare the proportions of those exposed among affected and unaffected individuals based on a survey carried out for this purpose, or on data from reliable available records' [Foratini, 1986].
Population
The study population consisted of 226 workers, 166 of whom were occupationally exposed to lead in battery factories or in battery rebuilding (exposed group), whereas the remaining 60 were not exposed to lead or to any other nephrotoxic chemicals (control group).
The criteria for inclusion in the study were as follows: (I) no history of renal disease (serum creatinine of less than 1.5 mg/dl) or diabetes mellitus; (2) no other activity involving the possibility of occupational exposure to other chemicals (mixed exposure); (3) no use of medication during the 30 d preceding collection of the material; (4) for the exposed groups, only individuals with stable employment with uninterrupted (nonintermittent) exposure to lead were selected; (5) non-smokers.
The following data were recorded for the individuals selected for the study: age, race, duration of exposure, weight, height, family income, and smoking habit. The exposed group ranged in age from 18 to 60 years, with a median of 33 years, and the control group ranged in age from 18 to 58 years, with a median of 33.5 years. Race distribution was as follows: 6.6% Blacks, 1 1.7% Mulattos, and 8 1.7% Whites in the exposed group, and 7.2% Blacks, 9.0% Mulattos, and 83.8% Whites in the control group. Family income ranged from two to five monthly minimum wages, corresponding to $80 to 400 per month.
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Methods
Blood pressure was measured three times at 5 min intervals on the day of sample collection, with the subject lying supine. A digital sphygmomanometer previously calibrated was used and systolic and diastolic pressures were recorded. The mean blood pressure (MBP) was calculated as follows.
Blood. In a field station at the workplace, approximately 7.0 ml of blood was collected in the morning before working hours using disposable plastic syringes and heparin as anticoagulants. Previous tests in our laboratory have shown that this procedure prevents contamination. The samples were stored in a refrigerator at 0 to 4°C for a maximum of 3d.
Urine. Urine samples (second voiding) were collected at the workplace into polyethylene bottles previously washed with diluted nitric acid and thoroughly rinsed with distilled and deionized water. No preservative was used and the urine samples were immediately frozen and analyzed within a maximum of 5 d.
Laboratory Analysis
Blood lead (B-Pb) was measured according to the method recommended by NIOSH [1984].
Urinary 8-aminolevulinic acid (U-ALA) was determined according to the method proposed by Tomokuni and Ogata [1972].
Urine and serum creatinine were assayed using reagents supplied by DOLES REAGENTS.
The activity of urinary N-acetyl-P-D-glucosaminidase (U-NAG; EC 3.2.1.30) was assessed by the method of Meyer et al. [1984].
The activity of urinary y-glutamyl-transpeptidase (U-yGT; EC 2.3.2.2) was assaid using reagents supplied by DOLES REAGENTS, while that of urinary alanine-aminopeptidase (U-AAP; EC 3.4.11.2) used the method of Jung and Scholz [19801. Urine albumin (U-ALB) measurements used reagents provided by LAB TEST Sistemas para Diagnbstico, and total protein in urine was assayed by the method of Hartree [1972].
Statistical Analysis of the Data
Data were analyzed statistically by nonparametric tests using the Statigraphics program (Statistical Graphics Corporation, STSC, Inc.). Nonparametric tests were chosen as a function of the results obtained since, in some cases, the hypothesis of data normality was not accepted.
Data were described using the third percentile, median, and 97th percentile. Comparison between groups was performed by the Mann-Whitney test, with the level of significance set at p< 0.05. Correlations were tested by the Spearman correlation coefficient.
RESULTS
Table I shows that there was no significant difference between groups in terms of age, weight, height, body mass index, systolic pressure, and mean pressure, but that there was a significant difference in diastolic pressure. The median pressures of the exposed group were also higher than those of the control group.
There was also a significant difference between groups in B-Pb, U-ALA, and U-NAG. Three workers in the exposed group had B-Pb>100 pg/IOO ml and 39.2% of this group presented B-Pb > 40 μg/ 100 ml. The highest B-Pb value detected in the control group was 22.5 μg/l00 ml. No differences in U-AAP, U-yGT, U-ALB, and total protein in urine were detected between the groups.
Correlation
The Spearman correlation coefficient (Table II) showed a statistically significant correlation between systolic pressure and duration of exposure to lead and B-Pb; between diastolic pressure and duration of exposure to lead, B-Pb, and U-ALA; between mean pressure and duration of exposure to lead, and B-Pb. Duration of exposure was significantly correlated with B-Pb, U-ALA, U-NAG, systolic, diastolic, and mean blood pressure. Blood lead was significantly correlated with U-ALA, U-NAG, and systolic, diastolic, and mean blood pressure. For the variables studied (U-AAP, U-TCT, U-ALB, and total protein in urine) which are not shown in Table II, there were no statistically significant correlations.
Multiple Regression
To explore and classify the numerous joint relationships existing between the variables under study and arterial pressure, we used the multiple linear regression model. To obtain the equation which best fit the data, we used the stepwise method and the following results were obtained:
log (systolic pressure) = 4.6022 - 0.0031 (age) + 0.0001 (age)2 + 0.0031 weight + 0.005 (duration of exposure);
log (diastolic pressure) = 4.0734 + 0.0022 (age) + 7.7384 X lop-6 (age)2 + 0.0091 body mass + 0.0058 (duration of exposure).
The square correlation coefficients (r2) obtained by these models were 0.229 and 0.248, respectively. Age, body mass index and weight were selected for the model as in the United States National Health and Nutrition Examination Survey (NHANES-11) [Pirkle et a]., 198.51. Age squared was selected because of the existence of a curvilinear relationship between arterial pressure and age. If the duration of lead exposure is removed from the model, B-Pb will be the variable selected by the process in the systolic pressure equation, and B-Pb, U-ALA, and U-NAG will be the variables selected by the process in the diastolic pressure equation, with the following results:
log (systolic pressure) = 4.5075 + 0.0006 age + 0.00003 (age)2 + 0.0033 weight + 0.0011 B-Pb;
log (diastolic pressure) = 3.969 + 0.0051 (age) - 0.00002 (age2) + 0.001 1 Pb - 0.0033 U-ALA + 0.0226 U-NAG + 0.010 body mass index.
B-Pb is not included in the model when we have a duration of exposure as a predictive variable. Age squared was selected by the stepwise process and age was forced into the model to remove possible age effects on arterial pressure.
The variables implied (r2) by these models were 0.1908 and 0.2010.
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DISCUSSION
Chronic lead nephropathy is of an insidious nature, with kidney damage going from a reversible to an irreversible phase. Only when glomerular filtration is reduced to approximately 25% of the normal value do the symptoms of the renal disease become visible [Dieperink, 19891. Our objective when excluding from the study individuals with creatinine in serum > 1.50 mg/dl was to select only workers with normal renal function since we intended to study the effect of chronic exposure to lead during a still preclinical phase. Diabetes, in turn, might also have acted as a confounding factor.
Our decision to exclude individuals undergoing clinical treatment was due to the possible interference of drugs with enzymuria. There were 16 hypertensive individuals who could not be used because, in addition to antihypertensive drugs, they also took other medications (analgesics, anti-inflammatory agents, antibiotics, and anti-dystonic drugs). By including these individuals, we would have impaired the analysis of the tests of renal function used.
The relationship between blood lead and blood pressure has a history full of contradictions both in studies of occupational exposure and of chronic environmental exposure to low concentrations [Sharp et al., 19881. The two most extensive studies on the correlation between nonoccupational exposure to lead and the occurrence of hypertension were the National Health and Nutrition Examination Survey (NHANES-II), carried out on the American population from 1976 to 1980, and the Regional Heart Study in Great Britain. The first, involving approximately 9,000 individuals, showed that after the proper adjustments for age, body mass index, nutritional factors, and biochemical blood tests using multiple regression models, there was a statistically significant relationship between systolic and diastolic blood pressure and blood lead (p < 0.01) in white men aged 20 to 74 years [Schwartz, 1988, 1991].
In the second study, conducted on 7,735 men aged 40 to 52 years in 24 British cities, a weak association was observed between blood lead and diastolic pressure, and a 1.45 mmHg increase in systolic pressure was estimated to occur by doubling the level of lead in blood, with a range of 0.47 to 2.73 mmHg and a 95% confidence limit [Pocock et al., 1988].
Another study [Staessen et al., 19901 surveyed 398 men and 133 women not occupationally exposed to heavy metals. The concentration of lead in blood was correlated with systolic and diastolic blood pressure, but the correlation was not statistically significant, and the concentration did not become biologically important after adjustments were made with respect to alcohol ingestion and other pertinent factors.
The same contradictions were observed among occupationally exposed individuals. Cramer and Dahlberg [ 19661 tested 364 workers in a battery factory and classified them into two groups, a lead affected group and a lead unaffected group, and found no statistically significant differences between them in terms of arterial pressure. Ramirez-Cervantes et al. [1978] studied 652 lead foundry workers with at least 5 years of exposure and found no differences in systolic and diastolic blood pressure. In another study, Parkinson et al. [1987] examined the relationship between occupational exposure to lead and diastolic and systolic blood pressure in 270 exposed and 158 non-exposed individuals. After considering factors such as age, education, smoking habit, alcohol ingestion, and physical activity, they concluded that the association between exposure to lead and blood pressure was weak and nonsignificant.
On the other side, a study conducted on a group of 53 workers occupationally exposed to lead showed that systolic and diastolic pressures were comparable to those of a group of 52 workers not exposed to metals, but mean blood pressure was higher in the exposed group (p < 0.05). The prevalence of hypertension was higher in the exposed group but the relative risk observed was not statistically significant (relative risk=1.91, 95%; confidence limit, 0.90-4.05) [de Kort et a]., 19871. In a second study cited by Neri et al. [ 19881 on workers in a lead foundry, an association detected between short-term changes in individual blood lead level and simultaneous changes in diastolic pressure remained significant after allowance for age (or time) trends and for effects attributable to changes in body weight.
In our study, we found a statistically significant difference related to diastolic (p < 0.05) but not to systolic pressure. These results agree with those obtained by Neri et al. [I9881 and Harlan [1988], agree in part with those obtained by de Kort et al. [ 19871, who also observed differences in systolic pressure, and disagree with those reported by Weiss et al. [ 19861, which suggested an association between exposure to lead and systolic pressure. The greater prevalence of hypertension among exposed individuals (32.2% vs. 20.4%) was basically due to the larger number of cases of diastolic hypertension (18.6% in the exposed group vs. 6.7% in the control group). However, when analyzing the correlations between blood lead and systolic and diastolic pressure, we obtained correlations with both variables, although the correlation with diastolic pressure was more significant.
Since blood pressure is a very complex parameter affected by many endogenous and exogenous factors, and considering factors such as age and body mass index in the regression analysis by the stepwise method, the predictive value was the duration of exposure to lead and not lead levels in the blood. This fact suggests that duration of exposure is a predominant factor in the development of hypertension, reflecting in a more effective manner the biological effect produced by lead, which is longer lasting and perhaps even irreversible. In contrast, blood lead levels only reflect a transitory state; they cannot be explored for previous exposures and do not reflect total body lead unless techniques of stored lead mobilization are employed. Duration of exposure was also correlated with blood lead levels (age?).
Previous studies on cardiovascular mortality under conditions of moderate exposure to lead have suggested that kidney damage was the etiological factor involved in the association between lead and hypertension [Emmerson, 1973; Batuman et al., 19831. Other studies did not demonstrate an action of lead on renal function at moderate levels of exposure [ Buchet et al., 1980; Omae et al., 19901. However, most of these studies used indicators considered to be of limited sensitivity for the detection of discrete reduction in renal function, taking into consideration the enormous functional reserve of the kidney [Lauwerys and Bernard, 19871. In this respect, determinations of urinary enzyme activities have proved to be more sensitive indicators of renal damage before functional kidney alterations are detected clinically [Mueller et al., 19891. Meyer et al. [1984] and Verschoor et al. [ 19871 observed an increase in U-NAG excretion in workers exposed to lead, but this was not confirmed by Cardenas et al. [1993].
Our results show that the activity of U-NAG was higher in the exposed group (p < 0.05), but no significant differences between exposed and control workers were found with respect to U-AAP or to U-yCT. In contrast to the study by Verschoor et al. [ 19871, we found a positive correlation between the duration of exposure to lead and U-NAG activity.
Uncertainty persists about whether chronic exposure to lead causes hypertension and hypertension induces renal damage, or whether lead accumulation in the kidneys induces subclinical renal dysfunction, which in turn leads to hypertension or, yet again, whether these effects are not related to one another [Sharp et a]., 19881. The absence of correlation between enzymuria and blood pressure detected in the present study suggests that the effects of lead on blood pressure and the kidney are independent and that they do not reflect the extent of renal involvement, at least during the initial stages of lead actors.
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ACKNOWLEDGMENTS
We gratefully acknowledge Prof. L. Larini and Prof. P. E. T. Salgado (School of Pharmaceutical Sciences of Araraquara, UNESP), Prof. H. V. Della Rosa (School of Pharmaceutical Sciences, USP), and Prof. J. R. Comes (School of Public Health, USP) for their comments, and Mrs. S. H. Abbade for typing the manuscript.
From: ' Occupational Exposure to Lead, Kidney Function Tests, and Blood Pressure' by Antonio Cardozo dos Santos, et al
---American Journal of Industrial Medicine 26:635443 (1994)
